Child care, socio-economic status and problem behavior: a study of gene-environment interaction in young Dutch twins.

The influences of formal child care before age 4 on behavioral problems at 3, 5, and 7 years of age were assessed in 18,932 Dutch twins (3,878 attended formal child care). The effect of formal child care was studied on the average level of problem behavior and as moderator of genetic and non-genetic influences, while taking into account effects of sex and parental socio-economic status (SES). There was a small association between attending formal child care and higher externalizing problems, especially when SES was low. Heritability was lower for formal child care and in lower SES conditions. These effects were largest at age 7 and for externalizing problems. In 7 year-old boys and girls, the difference in heritability between the formal child care group of low SES and the home care group of high SES was 30% for externalizing and ~20% for internalizing problems. The decrease in heritability was explained by a larger influence of the environment, rather than by a decrease in genetic variance. These results support a bioecological model in which heritability is lower in circumstances associated with more problem behavior.

The Young Netherlands Twin Register (YNTR): longitudinal twin and family studies in over 70,000 children.

The Netherlands Twin Register (NTR) began in 1987 with data collection in twins and their families, including families with newborn twins and triplets. Twenty-five years later, the NTR has collected at least one survey for 70,784 children, born after 1985. For the majority of twins, longitudinal data collection has been done by age-specific surveys. Shortly after giving birth, mothers receive a first survey with items on pregnancy and birth. At age 2, a survey on growth and achievement of milestones is sent. At ages 3, 7, 9/10, and 12 parents and teachers receive a series of surveys that are targeted at the development of emotional and behavior problems. From age 14 years onward, adolescent twins and their siblings report on their behavior problems, health, and lifestyle. When the twins are 18 years and older, parents are also invited to take part in survey studies. In sub-groups of different ages, in-depth phenotyping was done for IQ, electroencephalography , MRI, growth, hormones, neuropsychological assessments, and cardiovascular measures. DNA and biological samples have also been collected and large numbers of twin pairs and parents have been genotyped for zygosity by either micro-satellites or sets of short nucleotide polymorphisms and repeat polymorphisms in candidate genes. Subject recruitment and data collection is still ongoing and the longitudinal database is growing. Data collection by record linkage in the Netherlands is beginning and we expect these combined longitudinal data to provide increased insights into the genetic etiology of development of mental and physical health in children and adolescents.

Effects of chorionicity and zygosity on triplet birth weight.

Birth weight in triplets is, on average, lower than in singletons and twins, and more children are classified as having very low or extremely low birth weight. Still, there is limited research on factors that affect triplet birth weight, and samples under study are often small. Chorionicity and zygosity influence triplet birth weight, but it is unknown whether the effect of zygosity can be entirely ascribed to the effect of chorionicity or whether zygosity has an additional effect on triplet birth weight. This question was investigated in 346 triplets (from 116 trios) registered with the Netherlands Twin Register for whom data on chorionicity were available. 'Triplet' refers to one child and the set of three triplets is referred to as 'trio'. Trios and triplets were classified based on zygosity and chorionicity. With regression analysis, the effects of zygosity and chorionicity on triplet birth weight were examined, while controlling for gestational age, sex, and maternal smoking during pregnancy. In addition, within the dizygotic trios a within-family comparison was made between the birth weight of the triplets that were part of a monozygotic pair (with some pairs sharing a chorion), and the birth weight of the dizygotic triplet. Based on the classification on individual level, monozygotic, monochorionic triplets had a lower mean birth weight than dizygotic, dichorionic triplets. Most remarkably, in dizygotic trios, monozygotic pairs only had a lower mean birth weight than their dizygotic sibling triplet when the pair shared a chorion. We conclude that having shared a chorion, rather than being monozygotic, increases the risk of a low birth weight.

Gene-environment interaction in teacher-rated internalizing and externalizing problem behavior in 7- to 12-year-old twins.

BACKGROUND: Internalizing and externalizing problem behavior at school can have major consequences for a child and is predictive for disorders later in life. Teacher ratings are important to assess internalizing and externalizing problems at school. Genetic epidemiological studies on teacher-rated problem behavior are relatively scarce and the reported heritability estimates differ widely. A unique feature of teacher ratings of twins is that some pairs are rated by different and others are rated by the same teacher. This offers the opportunity to assess gene-environment interaction. METHODS: Teacher ratings of 3,502 7-year-old, 3,134 10-year-old and 2,193 12-year-old twin pairs were analyzed with structural equation modeling. About 60% of the twin pairs were rated by the same teacher. Twin correlations and the heritability of internalizing and externalizing behavior were estimated, separately for pairs rated by the same and different teachers. Socioeconomic status and externalizing behavior at age 3 were included as covariates. RESULTS: Twin correlations and heritability estimates were higher when twin pairs were in the same class and rated by the same teacher than when pairs were rated by different teachers. These differences could not be explained by twin confusion or rater bias. When twins were rated by the same teacher, heritability estimates were about 70% for internalizing problems and around 80% in boys and 70% in girls for externalizing problems. When twins were rated by different teachers, heritability estimates for internalizing problems were around 30% and for externalizing problems around 50%. CONCLUSIONS: Exposure to different teachers during childhood may affect the heritability of internalizing and externalizing behavior at school. This finding points to gene-environment interaction and is important for the understanding of childhood problem behavior. In addition, it could imply an opportunity for interventions at school.

Birth weight in a large series of triplets.

BACKGROUND: Triplets are often born premature and with a low birth weight. Because the incidence of triplet births is rare, there are relatively few studies describing triplet birth weight characteristics. Earlier studies are often characterized by small sample sizes and lack information on important background variables such as zygosity. The objective of this study is to examine factors associated with birth weight in a large, population-based sample of triplets registered with the Netherlands Twin Register (NTR). METHODS: In a sample of 1230 triplets from 410 families, the effects of assisted reproductive techniques, zygosity, birth order, gestational age, sex, maternal smoking and alcohol consumption during pregnancy on birth weight were assessed. The resemblance among triplets for birth weight was estimated as a function of zygosity. Birth weight discordance within families was studied by the pair-wise difference between triplets, expressed as a percentage of the birth weight of the heaviest child. We compare data from triplets registered with the NTR with data from population records, which include live births, stillbirths and children that have deceased within days after birth. RESULTS: There was no effect of assisted reproductive techniques on triplet birth weight. At gestational age 24 to 40 weeks triplets gained on average 130 grams per week; boys weighed 110 grams more than girls and triplets of smoking mothers weighted 104 grams less than children of non-smoking mothers. Monozygotic triplets had lower birth weights than di- and trizygotic triplets and birth weight discordance was smaller in monozygotic triplets than in di- and trizygotic triplets. The correlation in birth weight among monozygotic and dizygotic triplets was 0.42 and 0.32, respectively. In nearly two-thirds of the families, the heaviest and the lightest triplet had a birth weight discordance over 15%. The NTR sample is representative for the Dutch triplet population that is still alive 28 days after birth. CONCLUSION: Birth weight is an important determinant of childhood development. Triplet status, gestational age, sex, zygosity and maternal smoking affect birth weight. The combined effects amount to a difference of 364 grams between monozygotic girl triplets of smoking mothers compared to dizygotic boy triplets of non-smoking mothers of the same gestational age. Birth weight in triplets is also influenced by genetic factors, as indicated by a larger correlation in monozygotic than in di- and trizygotic triplets.

Heritability of anxious-depressive and withdrawn behavior: age-related changes during adolescence.

OBJECTIVE: To explain the differential course of anxiety and depression in individuals from childhood to adulthood by examining age-related changes in the genetic and environmental etiology of anxious and depressive symptoms. METHOD: A sample of 1470, 1839, and 2023 Dutch twins aged 12, 14, and 16 years reported on symptoms of anxious depression (AD) and withdrawn behavior (WB), using the Youth Self Report (YSR). AD and WB were analyzed with bivariate cross-sectional genetic models for each age group to obtain estimates of the relative influence of genes (A), shared (C), and nonshared (E) environment. RESULTS: The best-fitting models revealed no difference between heritability estimates in boys and girls. Familial clustering at age 12 years was explained by genetic and shared environmental factors. At ages 14 and 16 years, genetic factors were sufficient to explain familial clustering, shared environmental effects were absent. Genetic influences on AD and WB correlated highly. CONCLUSIONS: These findings are in agreement with earlier studies on age-specific effects of genes and shared environment on anxiety, depression, and withdrawn behavior in childhood and adolescence. The current study demonstrated that the decrease in the role of shared environment occurs after age 12. Hormonal changes accompanying the onset of puberty do not seem to explain the change in risk factors, as in 90% of the subjects puberty had already started. More knowledge on age-specific risk factors may offer opportunities for therapeutic interventions.

Extending acute trials to remote populations: a pilot study during interhospital helicopter transfer.

BACKGROUND AND PURPOSE: Methods to increase recruitment into acute stroke trials are needed. The purposes of this study were to evaluate the safety and acceptability of initiating acute stroke trials during early helicopter evacuation and to test an intervention to facilitate informed consent. METHODS: A randomized, controlled trial was done with patients with acute stroke who were transferred by helicopter to the University of Iowa Hospitals and Clinics from February 2007 to January 2008. The intervention to be evaluated was the use of fax and a telephone call to the patient/surrogate ahead of helicopter arrival at the outside emergency department. The aim was to improve the rate of subsequent consent (primary outcome) for a pilot trial of a potentially beneficial, low-risk medical intervention (ranitidine) to prevent aspiration pneumonitis. Consenting eligible patients received the infusion during the flight to University of Iowa Hospitals and Clinics. RESULTS: One hundred patients were enrolled. Consent rate was 54% in the intervention group and 50% in the control group (P=0.69). However, the consent rate was higher (69%) when prearrival communications between the coinvestigator and potential subjects were successful (P=0.04). This approach resulted in an average gain of 59 minutes as compared with initiating recruitment on arrival to University of Iowa Hospitals and Clinics. CONCLUSIONS: Enrollment into stroke intervention trials is feasible during helicopter transportation from a community hospital emergency department to a tertiary stroke center. This underused resource may improve trial efficiency by enabling and expediting participation of remote populations currently excluded from research. Consent rates might be further improved by communication strategies that are more successful in reaching patients at outside emergency departments.

Feasibility of acute clinical trials during aerial interhospital transfer.

BACKGROUND AND PURPOSE: In rural America, patients are often first seen at a small community hospital and then transferred to a tertiary care center by helicopter for further care. If acute clinical research were feasible during the aerial interhospital transport, more patients might be enrolled in trials at a critical earlier stage. METHODS: Prospective data were collected for all aerial transfers of a university-based helicopter service from April 2005 to January 2006. Flight nurses were educated about stroke research and offered certification and participation. Data collected included patient characteristics and the availability of relatives to provide surrogate consent. RESULTS: All 12 flight nurses completed the institutional review board certification requirements and collected data on 215 transfers. Sixty-one patients had acute stroke or myocardial events (MIs). The median time from symptom onset to helicopter arrival at an outside hospital was 213 minutes (range, 90 to 2135) for ischemic stroke (n=12), 186 (45 to 1332) for intracranial hemorrhage (n=28), and 157 (47 to 1044) for MI (n=21). A relative was available in >74% of those transfers. A trial with a 4-hour window would permit enrollment of 67% of the ischemic strokes, 82% of intracranial hemorrhage cases, and 76% of MI patients. CONCLUSIONS: Clinical trials are feasible during aerial interhospital transport of patients. Flight nurses became successful investigators in clinical research and were exposed to potentially eligible patients with the ability to consent either directly or through surrogates. This approach could improve current clinical trial recruitment in rural areas, as well as permit testing of inflight ancillary interventions to improve outcome during patient transport.