Genetic Epidemiology of Attention Deficit Hyperactivity Disorder (ADHD Index) in Adults

Context: In contrast to the large number of studies in children, there is little information on the contribution of genetic factors to Attention Deficit Hyperactivity Disorder (ADHD) in adults. Objective: To estimate the heritability of ADHD in adults as assessed by the ADHD index scored from the CAARS (Conners’ Adult ADHD Rating Scales). Design: Phenotype data from over 12,000 adults (twins, siblings and parents) registered with the Netherlands Twin Register were analyzed using genetic structural equation modeling. Main outcome measures: Heritability estimates for ADHD from the twin-family study. Results: Heritability of ADHD in adults is estimated around 30 % in men and women. There is some evidence for assortative mating. All familial transmission is explained by genetic inheritance, there is no support for the hypothesis that cultural transmission from parents to offspring is important. Conclusion: Heritability for ADHD features in adults is present, but is substantially lower than it is in children

Phase-rectified signal averaging method to predict perinatal outcome in infants with very preterm fetal growth restriction- a secondary analysis of TRUFFLE-trial

BACKGROUND: Phase-rectified signal averaging, an innovative signal processing technique, can be used to investigate quasi-periodic oscillations in noisy, nonstationary signals that are obtained from fetal heart rate. Phase-rectified signal averaging is currently the best method to predict survival after myocardial infarction in adult cardiology. Application of this method to fetal medicine has established significantly better identification than with short-term variation by computerized cardiotocography of growth-restricted fetuses. OBJECTIVE: The aim of this study was to determine the longitudinal progression of phase-rectified signal averaging indices in severely growth-restricted human fetuses and the prognostic accuracy of the technique in relation to perinatal and neurologic outcome. STUDY DESIGN: Raw data from cardiotocography monitoring of 279 human fetuses were obtained from 8 centers that took part in the multicenter European “TRUFFLE” trial on optimal timing of delivery in fetal growth restriction. Average acceleration and deceleration capacities were calculated by phase-rectified signal averaging to establish progression from 5 days to 1 day before delivery and were compared with short-term variation progression. The receiver operating characteristic curves of average acceleration and deceleration capacities and short-term variation were calculated and compared between techniques for short- and intermediate-term outcome. RESULTS: Average acceleration and deceleration capacities and short-term variation showed a progressive decrease in their diagnostic indices of fetal health from the first examination 5 days before delivery to 1 day before delivery. However, this decrease was significant 3 days before delivery for average acceleration and deceleration capacities, but 2 days before delivery for short-term variation. Compared with analysis of changes in short-term variation, analysis of (delta) average acceleration and deceleration capacities better predicted values of Apgar scores <7 and antenatal death (area under the curve for prediction of antenatal death: delta average acceleration capacity, 0.62 [confidence interval, 0.19–1.0]; delta short-term variation, 0.54 [confidence interval, 0.13–0.97]; P=.006; area under the curve for prediction Apgar <7: average deceleration capacity <24 hours before delivery, 0.64 [confidence interval, 0.52–0.76]; short-term variation <24 hours before delivery, 0.53 [confidence interval, 0.40–0.65]; P=.015). Neither phase-rectified signal averaging indices nor short-term variation showed predictive power for developmental disability at 2 years of age (Bayley developmental quotient, <95 or <85). CONCLUSIONS: The phase-rectified signal averaging method seems to be at least as good as short-term variation to monitor progressive deterioration of severely growth-restricted fetuses. Our findings suggest that for short-term outcomes such as Apgar score, phase-rectified signal averaging indices could be an even better test than short-term variation. Overall, our findings confirm the possible value of prospective trials based on phase-rectified signal averaging indices of autonomic nervous system of severely growth-restricted fetuses

Do differences in diagnostic criteria for late fetal growth restriction matter?

Background: Criteria for diagnosis of fetal growth restriction differ widely according to national and international guidelines, and further heterogeneity arises from the use of different biometric and Doppler reference charts, making the diagnosis of fetal growth restriction highly variable. Objective: This study aimed to compare fetal growth restriction definitions between Delphi consensus and Society for Maternal-Fetal Medicine definitions, using different standards/charts for fetal biometry and different reference ranges for Doppler velocimetry parameters. Study design: From the TRUFFLE 2 feasibility study (856 women with singleton pregnancy at 32+0 to 36+6 weeks of gestation and at risk of fetal growth restriction), we selected 564 women with available mid-pregnancy biometry. For the comparison, we used standards/charts for estimated fetal weight and abdominal circumference from Hadlock, INTERGROWTH-21st, and GROW and Chitty. Percentiles for umbilical artery pulsatility index and its ratios with middle cerebral artery pulsatility index were calculated using Arduini and Ebbing reference charts. Sensitivity and specificity for low birthweight and adverse perinatal outcome were evaluated. Results: Different combinations of definitions and reference charts identified substantially different proportions of fetuses within our population as having fetal growth restriction, varying from 38% (with Delphi consensus definition, INTERGROWTH-21st biometric standards, and Arduini Doppler reference ranges) to 93% (with Society for Maternal-Fetal Medicine definition and Hadlock biometric standards). None of the different combinations tested appeared effective, with relative risk for birthweight <10th percentile between 1.4 and 2.1. Birthweight <10th percentile was observed most frequently when selection was made with the GROW/Chitty charts, slightly less with the Hadlock standard, and least frequently with the INTERGROWTH-21st standard. Using the Ebbing Doppler reference ranges resulted in a far higher proportion identified as having fetal growth restriction compared with the Arduini Doppler reference ranges, whereas Delphi consensus definition with Ebbing Doppler reference ranges produced similar results to those of the Society for Maternal-Fetal Medicine definition. Application of Delphi consensus definition with Arduini Doppler reference ranges was significantly associated with adverse perinatal outcome, with any biometric standards/charts. The Society for Maternal-Fetal Medicine definition could not accurately detect adverse perinatal outcome irrespective of estimated fetal weight standard/chart used. Conclusion: Different combinations of fetal growth restriction definitions, biometry standards/charts, and Doppler reference ranges identify different proportions of fetuses with fetal growth restriction. The difference in adverse perinatal outcome may be modest, but can have a significant impact in terms of rate of intervention

Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study

<p>Abstract</p> <p>Background</p> <p>Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy.</p> <p>Methods/Design</p> <p>The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.</p> <p>Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).</p> <p>Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.</p> <p>We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test_2-sided). Analysis will be by intention to treat and it allows for one interim analysis.</p> <p>Discussion</p> <p>In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia.</p> <p>Trial registration number</p> <p>Clinical Trials, protocol registration system: NCT00189007</p

Childhood behaviour problems show the greatest gap between DNA-based and twin heritability

For most complex traits, DNA-based heritability (‘SNP heritability’) is roughly half that of twin-based heritability. A previous report from the Twins Early Development Study suggested that this heritability gap is much greater for childhood behaviour problems than for other domains. If true, this finding is important because SNP heritability, not twin heritability, is the ceiling for genome-wide association studies. With twice the sample size as the previous report, we estimated SNP heritabilities (N up to 4653 unrelated individuals) and compared them with twin heritabilities from the same sample (N up to 4724 twin pairs) for diverse domains of childhood behaviour problems as rated by parents, teachers, and children themselves at ages 12 and 16. For 37 behaviour problem measures, the average twin heritability was 0.52, whereas the average SNP heritability was just 0.06. In contrast, results for cognitive and anthropometric traits were more typical (average twin and SNP heritabilities were 0.58 and 0.28, respectively). Future research should continue to investigate the reasons why SNP heritabilities for childhood behaviour problems are so low compared with twin estimates, and find ways to maximise SNP heritability for genome-wide association studies

Twenty years of stereotype threat research: A review of psychological mediators

This systematic literature review appraises critically the mediating variables of stereotype threat. A bibliographic search was conducted across electronic databases between 1995 and 2015. The search identified 45 experiments from 38 articles and 17 unique proposed mediators that were categorized into affective/subjective (n = 6), cognitive (n = 7) and motivational mechanisms (n = 4). Empirical support was accrued for mediators such as anxiety, negative thinking, and mind-wandering, which are suggested to co-opt working memory resources under stereotype threat. Other research points to the assertion that stereotype threatened individuals may be motivated to disconfirm negative stereotypes, which can have a paradoxical effect of hampering performance. However, stereotype threat appears to affect diverse social groups in different ways, with no one mediator providing unequivocal empirical support. Underpinned by the multi-threat framework, the discussion postulates that different forms of stereotype threat may be mediated by distinct mechanisms

The Relationship of DNA Methylation with Age, Gender and Genotype in Twins and Healthy Controls

Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease

Heritability of Self-reported Phobic Fear

Twin studies on fear and phobia suggest moderate genetic effects. However, results are inconclusive regarding the presence of dominant genetic effects and sex differences. Using an extended twin design, including male and female twins (n = 5,465) and their siblings (n = 1,624), we examined the genetic and environmental influences on blood-injury, social, and agoraphobic fear and investigated their interaction with sex and age. Data of spouses (n = 708) of twins were used to evaluate assortative mating for the three fear dimensions. Results showed that there was no assortative mating for blood-injury, social and agoraphobic fear. Resemblance between biological relatives could be explained by additive and non-additive genetic effects for blood-injury and agoraphobic fear in all participants, and social fear in participants aged 14–25 years. For social fear in participants aged 26–65 only additive genetic effects were detected. Broad-sense heritability estimates ranged from 36 to 51% and were similar for men and women

Gene Expression Profiles Characterize Inflammation Stages in the Acute Lung Injury in Mice

Acute Lung Injury (ALI) carries about 50 percent mortality and is frequently associated with an infection (sepsis). Life-support treatment with mechanical ventilation rescues many patients, although superimposed infection or multiple organ failure can result in death. The outcome of a patient developing sepsis depends on two factors: the infection and the pre-existing inflammation. In this study, we described each stage of the inflammation process using a transcriptional approach and an animal model. Female C57BL6/J mice received an intravenous oleic acid injection to induce an acute lung injury (ALI). Lung expression patterns were analyzed using a 9900 cDNA mouse microarray (MUSV29K). Our gene-expression analysis revealed marked changes in the immune and inflammatory response metabolic pathways, notably lipid metabolism and transcription. The early stage (1 hour–1.5 hours) is characterized by a pro-inflammatory immune response. Later (3 hours–4 hours), the immune cells migrate into inflamed tissues through interaction with vascular endothelial cells. Finally, at late stages of lung inflammation (18 hours–24 hours), metabolism is deeply disturbed. Highly expressed pro-inflammatory cytokines activate transcription of many genes and lipid metabolism. In this study, we described a global overview of critical events occurring during lung inflammation which is essential to understand infectious pathologies such as sepsis where inflammation and infection are intertwined. Based on these data, it becomes possible to isolate the impact of a pathogen at the transcriptional level from the global gene expression modifications resulting from the infection associated with the inflammation