Characterizing sleep disorders in an autism-specific collection of electronic health records.

OBJECTIVE/BACKGROUND: Sleep problems are common in people on the autism spectrum. This study reviews one detailed approach to querying the electronic health record (EHR) in a large tertiary care center. PATIENTS/METHODS: We developed methods for identifying people on the autism spectrum and defined their sleep problems using the key words, "sleep" or "melatonin", or International Classification of Diseases (ICD) codes. We examined treatment responses of these individuals to melatonin supplementation. RESULTS: Sleep problems were documented in 86% of patients with ages ranging from 6 to 30 years old. Our specific keyword search yielded more patients with sleep diagnoses than ICD codes alone. About two-thirds of patients who received melatonin supplementation reported benefit from its use. CONCLUSIONS: Our study provides a framework for using deidentified medical records to characterize sleep, a common co-occurring condition, in people on the autism spectrum. Using specific keywords could be helpful in future work that queries the EHR.

Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls.

BACKGROUND: Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders. METHODS: We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia. RESULTS: Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50. CONCLUSIONS: Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis.

Ataxin 2 binding protein 1 (A2BP1 aka FOX1, RBFOX1) is an RNA binding protein responsible for regulation of pre-mRNA splicing events in a number of critical developmental genes expressed in muscle, heart and neuronal cells [Shibata et al. (2000); Mamm Genome 12:595-601; Jin et al. (2003); EMBO J 22:905-912; Underwood et al. (2005); Mol Cell Biol 25:10005-10016]. Rare copy number abnormalities of A2BP1 have been previously associated with cognitive impairment, attention deficit disorder and autism [Martin et al. (2007); Am J Med Gen Part B 144B:869-876; Elia et al. (2010); Mol Psychiatry 15:637-646.]. Using a 1M Illumina SNP microarray, we identified a 1.3 kb deletion in A2BP1, which was subsequently validated by quantitative PCR. Here we present an in depth case study of an individual with autism and mild developmental hemiparesis in whom the deletion was detected. This study provides further support for the possible role of rare copy number variants in A2BP1 in the development of autism and associated motor asymmetries.

Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in Mozambique tilapia.

Like other fish species, Mozambique tilapia has three forms of estrogen receptor, ERα, ERß1, and ERß2. A primary function of 17ß-estradiol (E(2)) in oviparous species is the hepatic induction of the yolk precursor protein, vitellogenin (Vg). To characterize the roles of ERs in Vg production, transactivation assays and an in vivo study were carried out utilizing agonists for mammalian ERα and ERß, and an antagonist for mammalian ERα, propyl-pyrazole-triol (PPT), diarylpropionitrile (DPN), and methyl-piperidino-pyrazole (MPP), respectively. ERα was more sensitive and responsive to PPT than ERß1 or ERß2 in transactivation assays. All ER isoforms indicated equivalent responsiveness to DPN compared with E(2), although sensitivity to DPN was lower. MPP exhibited antagonistic action on transactivation of all ER isoforms and reduced the E(2) effect on Vg and ERα 48h post-injection. DPN increased ERα and Vg expression and plasma Vg post-injection, whereas PPT was without effect; DPN seems to stimulate Vg production through activation of ERα. The ligand binding domain of all tilapia ER forms shares only 60-65% amino acid identity with human ERα and ERß. This, together with our results, clearly indicates that agonistic or antagonistic characteristics of PPT, DPN and MPP cannot be extrapolated from mammalian to piscine ERs.

Acute salinity challenges in Mozambique and Nile tilapia: differential responses of plasma prolactin, growth hormone and branchial expression of ion transporters.

The responses of Mozambique and Nile tilapia acclimated to fresh water (FW) and brackish water (BW; 17 per thousand) were compared following acute salinity challenges. In both species, plasma osmolality increased to above 450 mOsm by 2h after transfer from FW to seawater (SW); these increases in osmolality were accompanied by unexpected increases in plasma prolactin (PRL). Likewise, PRL receptor gene expression in the gill also increased in both species. In Nile tilapia, hyperosmotic transfers (FW to BW and SW) resulted in increased plasma growth hormone (GH) and in branchial GH receptor gene expression, responses that were absent in Mozambique tilapia. Branchial gene expression of osmotic stress transcription factor 1 (OSTF1) increased in both species following transfer from FW to SW, whereas transfer from BW to SW induced OSTF1 expression only in the Nile tilapia. Branchial expression of Na(+)/Cl(-) cotransporter was higher in FW in both species than in BW. Branchial gene expression of Na(+)/K(+)/2Cl(-) cotransporter (NKCC) increased after transfer from BW to SW in Mozambique tilapia, whereas expression was reduced in the Nile tilapia following the same transfer. The difference in the SW adaptability of these species may be related to a limited capacity of Nile tilapia to up-regulate NKCC gene expression, which is likely to be an essential component in the recruitment of SW-type chloride cells. The differential responses of GH and OSTF1 may also be associated with the disparate SW adaptability of these two tilapiine species.

Novel copy number variants in children with autism and additional developmental anomalies.

Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip® (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone.

Pax6 3' deletion results in aniridia, autism and mental retardation.

The PAX6 gene is a transcription factor expressed early in development, predominantly in the eye, brain and gut. It is well known that mutations in PAX6 may result in aniridia, Peter's anomaly and kertatisis. Here, we present mutation analysis of a patient with aniridia, autism and mental retardation. We identified and characterized a 1.3 Mb deletion that disrupts PAX6 transcriptional activity and deletes additional genes expressed in the brain. Our findings provide continued evidence for the role of PAX6 in neural phenotypes associated with aniridia.

Prolactin receptor, growth hormone receptor, and putative somatolactin receptor in Mozambique tilapia: tissue specific expression and differential regulation by salinity and fasting.

In fish, pituitary growth hormone family peptide hormones (growth hormone, GH; prolactin, PRL; somatolactin, SL) regulate essential physiological functions including osmoregulation, growth, and metabolism. Teleost GH family hormones have both differential and overlapping effects, which are mediated by plasma membrane receptors. A PRL receptor (PRLR) and two putative GH receptors (GHR1 and GHR2) have been identified in several teleost species. Recent phylogenetic analyses and binding studies suggest that GHR1 is a receptor for SL. However, no studies have compared the tissue distribution and physiological regulation of all three receptors. We sequenced GHR2 from the liver of the Mozambique tilapia (Oreochromis mossambicus), developed quantitative real-time PCR assays for the three receptors, and assessed their tissue distribution and regulation by salinity and fasting. PRLR was highly expressed in the gill, kidney, and intestine, consistent with the osmoregulatory functions of PRL. PRLR expression was very low in the liver. GHR2 was most highly expressed in the muscle, followed by heart, testis, and liver, consistent with this being a GH receptor with functions in growth and metabolism. GHR1 was most highly expressed in fat, liver, and muscle, suggesting a metabolic function. GHR1 expression was also high in skin, consistent with a function of SL in chromatophore regulation. These findings support the hypothesis that GHR1 is a receptor for SL. In a comparison of freshwater (FW)- and seawater (SW)-adapted tilapia, plasma PRL was strongly elevated in FW, whereas plasma GH was slightly elevated in SW. PRLR expression was reduced in the gill in SW, consistent with PRL's function in freshwater adaptation. GHR2 was elevated in the kidney in FW, and correlated negatively with plasma GH, whereas GHR1 was elevated in the gill in SW. Plasma IGF-I, but not GH, was reduced by 4 weeks of fasting. Transcript levels of GHR1 and GHR2 were elevated by fasting in the muscle. However, liver levels of GHR1 and GHR2 transcripts, and liver and muscle levels of IGF-I transcripts were unaffected by fasting. These results clearly indicate tissue specific expression and differential physiological regulation of GH family receptors in the tilapia.

Elevated blood lead levels among adults in Massachusetts, 1991-1995.

OBJECTIVE: Lead poisoning, the oldest recognized occupational disease, remains a danger for children and adults. Data collected for 664 cases reported to the Massachusetts Occupational Lead Registry in 1991-1995 were summarized in a 1998 state report. Here, the authors present some of the key findings from that report for a wider audience. METHODS: The authors summarize key findings of the 1998 state report. FINDINGS: Construction workers, in particular licensed deleaders and house painters, accounted for almost 70% of occupational cases involving blood lead levels > or = 40 micrograms of lead per deciliter (mcg/dl) of blood. Among 100 workers with the highest blood lead levels (> or = 60 mcg/dl), 29% were house painters. Hispanic workers were over-represented in the Registry. A small proportion of cases were non-occupational, typically associated with recreational use of firing ranges or do-it-yourself home renovations. CONCLUSION: Lead poisoning is a preventable disease, yet these data indicate that additional prevention efforts are warranted.

Protecting youth at work.

The National Research Council's report "Protecting Youth at Work" addresses the health and safety consequences of work by youth in the United States. The report finds that a higher proportion of U.S. youth work than in any other developed nation and that as much as 80% of youth will have worked during their high school years. The majority of adolescents are employed in the retail and service sectors. Positive aspects of this work include lessons in responsibility, punctuality, dealing with people, good money management, and gaining self-esteem, independence and new skills. On the negative side, however, students who work long hours are less likely to advance as far in school as other students, are more likely to smoke cigarettes and use illegal drugs, be involved in other deviant behavior, may get insufficient sleep and exercise, and may spend less time with their family. Working youth appear to have injury rates (4.9 per 100 FTE) almost twice that of adult workers (2.8 per 100 FTE). There is evidence that each year over 200,000 youth experience work injuries and at least 70 die. The report includes an extensive list of recommendations to safeguard the health and well-being of young workers: improved government regulations as well as their enforcement, better data collection and analysis to provide essential information on the distribution and consequences of youth employment, education of key actors such as employers, parents, teachers and the youth themselves, and research to fill critical knowledge gaps.

Work-related injuries to Massachusetts teens, 1987-1990.

This study uses workers' compensation data to describe the work-related injury experience of Massachusetts teens, ages 14-17, from 1987 to 1990. During this period, 2,551 injuries were reported to the workers' compensation system. Injuries were more frequent among 16-17 year-olds and among males. Sprains and strains, followed by lacerations, were the most frequent type of injury. Four industries--grocery stores, restaurants, health services, and department stores--accounted for over half of all injuries. The overall injury rate was 1.9/100 full-time equivalents (FTEs), but was higher in the construction, manufacturing, and wholesale trade sectors. Teens working in apparel manufacturing and nursing homes sustained the highest rate of injuries. Geographical analysis indicated that teens living in the southeast region of the state had the highest injury rates. This study adds to the existing evidence that work-related injuries to teens are a substantial public health problem.

Elevated blood lead levels among construction workers in the Massachusetts Occupational Lead Registry.

Although the construction industry until recently was exempt from the Occupational Health and Safety Administration General Industry Lead Standard, including its medical monitoring provisions, periodic blood lead tests have been required for residential "deleaders" and structural painters in Massachusetts. Sixty-three percent of the 381 registrants in the Massachusetts Occupational Lead Registry with blood lead levels of 1.93 mumol/L or higher are construction workers. This proportion is much higher than that reported by registries of several states selected for comparison. These data highlight the need for better protection from lead exposure and the effectiveness of mandatory medical surveillance in identifying elevated blood lead levels among construction workers.

Use of state workers' compensation data for occupational carpal tunnel syndrome surveillance: a feasibility study in Massachusetts.

The purpose of this study was to determine the feasibility of using Massachusetts workers' compensation data for passive surveillance of occupational carpal tunnel syndrome (OCTS). Workers' compensation claims for OCTS (n = 358) and for possible cases of OCTS (n = 1,121) active during the first 6 months of 1989 were identified. The availability and distribution of demographic and employment descriptors were assessed. Medical records on a sample of the claims were reviewed to validate the diagnosis of OCTS. Age, gender, and occupation were available for less than 47% of the reported cases of OCTS. The majority (88%) of cases on whom medical record review was performed had a physician's diagnosis of carpal tunnel syndrome (CTS), and most of this group had confirmatory nerve conduction studies or electromyography. However, there were fundamental limitations to workers' compensation based disease surveillance in Massachusetts, including underascertainment of cases, potential ascertainment biases, delayed case reporting, limited access to specific diagnostic information, and incomplete and sometimes inaccurate information. These limitations are likely to be applicable in many, if not most, states and must be made clear in any analyses based on workers' compensation data.

Work-related injuries among Massachusetts children: a study based on emergency department data.

Millions of children in the United States work and, despite federal and state laws, face safety hazards. Previous studies have documented large numbers of injuries suffered on the job by working children. This study describes work-related injuries to children 14-17 years old in 14 Massachusetts communities (representing 5% of the state population) based on data from emergency departments and hospital admissions collected as part of a large population-based surveillance study of injuries to children and adolescents from 1979 to 1982. An estimated 1,176 work-related injuries occurred during the three-year period, accounting for 7-13% of all injury-related emergency department visits in this age group; the proportion among 17-year-olds was 14-26%. Cuts and lacerations were the most frequent type of injury, cutting/piercing was the most common cause, and cutting instruments were the most frequently identified products. Seventeen children were hospitalized for work-related injuries during the course of the study. The estimated annual rate of occupational injury rose from 3.7/1,000 children for 14- to 15-year-olds to 44.7/1000 for 17-year-olds; these rates count all resident children, regardless of their employment status, in the denominator. Rates based on actual hours worked are much higher, and strongly suggest that working minors should be considered a high-risk group for occupational injury. This study adds to the mounting evidence that work-related injuries to children are a significant public health problem and contribute significantly to the overall incidence of injuries among children 14-17 years old. The study also demonstrates the potential of emergency department data as a valuable source of information about work-related injuries to children. Active surveillance systems combining data from emergency departments, workers' compensation, and other potential sources should be established to fully document the nature and extent of the problem. Efforts to prevent these injuries will require the combined attention of employers, parents, medical providers, educators and regulators, as well as working children themselves.

Use of death certificates for mesothelioma surveillance.

Data from the Massachusetts Cancer Registry and death certificates were linked for mesothelioma cases reported to the registry from 1982 through 1987 to determine the extent to which the cause of death information that is given on the death certificate is useful in identifying mesothelioma cases for disease surveillance. Only 12 percent of all persons reported with mesothelioma who had died were detected using underlying cause of death codes for cancers of the peritoneum and pleura, which are commonly used to identify mesothelioma cases. The rate increased to 83 percent when death certificates were reviewed manually for any mention of mesothelioma. Surveillance using only the coded cause of death data currently available will result in a large underascertainment of mesothelioma cases.

Cancer incidence among Massachusetts firefighters, 1982-1986.

Previous investigations of cancer among firefighters have been limited to mortality data and have yielded inconsistent results. Case-control analyses were conducted in the present surveillance study in order to examine associations between firefighting and cancer incidence in Massachusetts. Subjects were identified through the Massachusetts Cancer Registry files for 1982-1986. Exposure status (firefighting) was determined from the usual occupation reported to the Registry. Nine different cancer types were examined among the 315 reported white male firefighters. Two "unexposed" reference populations were used: policemen and statewide males. Standardized morbidity odds ratios (SMORs) were statistically significantly elevated for melanoma (SMOR = 292; 95% C.I. = 170-503) and bladder cancer (SMOR = 159; 95% C.I. = 102-250) among firefighters compared with the state as a whole. When policemen were used as the reference group, the bladder cancer excess persisted (SMOR = 211; 95% C.I. = 107-414) and non-Hodgkin's lymphoma was elevated (SMOR = 327; 95% C.I. = 119-898); the melanoma excess was largely reduced (SMOR = 138; 95% C.I. = 60-319) but remained elevated among those aged 55-74 years (SMOR = 513; 95% C.I. = 150-1,750). Small number excesses (not significant) were also observed for pancreatic cancer and leukemia compared with police.