Hanna Mulder

Pharmacogenetics: from bench to byte--an update of guidelines.

Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics‐based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine‐S‐methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA‐B44, HLA‐B*5701, CYP3A5, and factor V Leiden (FVL).

Development of Executive Function and Attention in Preterm Children: A Systematic Review

We report on a systematic review of studies of executive function and attention in preterm children. Using meta-analysis, we confirm this is an area of weakness for preterm children, and show that the extent of difficulties is influenced by gestational age (GA), age at test, and skill under investigation. Effect size for selective and sustained attention and inhibition is related to GA. For studies with mean GA ≥ 26 weeks, selective attention skills catch up with age, phonemic fluency skills are increasingly delayed, and ongoing deviance is shown for shifting skills (when assessed with specific measures). Implications for research and practice are discussed.

Pharmacogenetics: From Bench to Byte

Despite initial enthusiasm, 1 , 2 , 3 the use of pharmacogenetics has remained limited to investigation in only a few clinical fields such as oncology and psychiatry. 4 , 5 , 6 , 7 , 8 The main reason is the paucity of scientific evidence to show that pharmacogenetic testing leads to improved clinical outcomes. 9 , 10 Moreover, for most pharmacogenetic tests (such as tests for genetic variants of cytochrome P450 enzymes) a detailed knowledge of pharmacology is a prerequisite for application in clinical practice, and both physicians and pharmacists might find it difficult to interpret the clinical value of pharmacogenetic test results. Guidelines that link the result of a pharmacogenetic test to therapeutic recommendations might help to overcome these problems, but such guidelines are only sparsely available. In 2001, an early step was taken to develop such guidelines for the therapeutic use of antidepressants, and these included CYP2D6‐related dose recommendations drawn from pharmacokinetic study data. 11 However, the use of such recommendations in routine clinical practice remains difficult, because they are currently outside the ambit of the clinical environment and are not accessible during the decision‐making process by physicians and pharmacists, namely the prescription and dispensing of drugs.

Processing speed and working memory underlie academic attainment in very preterm children

Aim To study the impact of specific neuropsychological measures on academic attainment in very preterm (VPT) children. Methods VPT children (gestational age <31 weeks, N=48) and matched term controls (N=17) aged 9–10 years were assessed with measures of processing speed, executive function and IQ. Teachers reported on academic achievement in a questionnaire. Results Group differences in academic attainment were significant for maths (OR 6.5; 95% CI 1.7 to 25.8), English/literacy (OR 3.8; 95% CI 1.1 to 13.5), overall academic attainment (OR 11.9; 95% CI 1.4 to 96.9) and special educational needs provision (OR 7.2; 95% CI 1.5 to 35.0). All significant group differences in attainment could be accounted for by processing speed. Birth group, processing speed and working memory were significant predictors of overall attainment (R2=0.57; p<0.001). Conclusions Processing speed and working memory are important factors underlying academic attainment in VPT children. Specific tests of processing speed and working memory, which together take approximately only 10 min to administer, could potentially be used as efficient screening instruments to assess which children are at risk of educational problems and should be referred for a full neuropsychological assessment.

Executive Functions in Preschool Children with Externalizing Behavior Problems: A Meta-Analysis

Deficits in executive functions (EF) have been found in school-age children and adolescents with externalizing behavior disorders. Present meta-analysis was carried out to determine whether these EF impairments can also be found in preschool children with externalizing behavior problems. Twenty-two studies were included with a total of 4021 children. Four separate meta-analyses were conducted, concerning overall EF, working memory, inhibition and cognitive flexibility. A medium correlation effect size was obtained for overall EF (ESzr = 0.22) and for inhibition (0.24), whereas a small effect size was found for working memory (0.17) and for cognitive flexibility (0.13). Moderator analyses revealed a stronger effect for older preschoolers compared to younger preschoolers, and for children from referred samples compared to community samples. These results show that EF, especially inhibition, is related to externalizing behavior problems already in preschool years.

Inattentive behaviour is associated with poor working memory and slow processing speed in very pre-term children in middle childhood

BACKGROUND. Problem behaviour is common following pre-term birth, but the underlying nature of these difficulties is not well known. AIMS. We sought to establish the mechanisms underpinning behavioural difficulties in very pre-term (VPT) children in middle childhood by comparing their performance to that of term born peers on tasks of working memory, inhibition, and processing speed, and relating these to parent and teacher assessments of their behaviour. Particular focus was given to inattention and overactive/impulsive behaviour, as these behaviours have been associated with different neuropsychological problems in term children. SAMPLES. A group of VPT children (gestational age < 31 weeks, N= 56) aged 9-10 years and term controls (N= 22) participated in the study. METHOD. Children were assessed with measures of working memory, inhibition, and processing speed. Parents and teachers reported behavioural problems using the Strengths and Difficulties Questionnaire and two additional scales measuring overactive/impulsive behaviour and inattention. RESULTS. Results revealed increased rates of problem behaviour in VPT compared to term children for parent-rated total difficulties, hyperactivity, emotional problems, peer problems, prosocial behaviour, overactive/impulsive behaviour, and parent- and teacher-rated inattention. Processing speed and working memory, but not inhibition, were significantly related to inattentive and overactive/impulsive behaviour. CONCLUSIONS. The increased rates of inattention and overactive/impulsive behaviour in VPT children may be explained by impairment in processing speed and working memory. Expected links between overactive/impulsive behaviour and inhibitory control were not identified, suggesting the nature of such difficulties may be different in VPT compared to term children.

Processing speed mediates executive function difficulties in very preterm children in middle childhood

Executive function and attention difficulties are reported in very preterm (VPT) children at school entry, but it is unclear if these remain at later ages and/or if these difficulties are mediated by more basic functions, such as processing speed. Processing speed has been shown to underlie academic and behavioral problems in VPT children in middle childhood (Mulder, Pitchford, & Marlow, 2010, 2011), so may also underpin executive function and attention difficulties. We investigated this by comparing VPT (gestational age <31 weeks; N = 56) to term children (N = 22) aged 9-10 years on a comprehensive battery of executive function and attention tasks from the Test of Everyday Attention for Children (Manly, Robertson, Anderson, & Nimmo-Smith, 1999) and NEPSY (Korkman, Kirk, & Kemp, 1998). Selective and sustained attention, inhibition, working memory, shifting, verbal fluency, planning, and processing speed were examined. Group differences favoring term children were shown on most executive function tasks (i.e., inhibition, working memory, verbal fluency, and shifting), all of which were mediated by slow processing speed in the VPT group, except response inhibition. Seemingly, processing speed is an important determinant underpinning many neuropsychological deficits seen in VPT children in middle childhood.

Psychometric properties and convergent and predictive validity of an executive function test battery for two-year-olds

Executive function (EF) is an important predictor of numerous developmental outcomes, such as academic achievement and behavioral adjustment. Although a plethora of measurement instruments exists to assess executive function in children, only few of these are suitable for toddlers, and even fewer have undergone psychometric evaluation. The present study evaluates the psychometric properties and validity of an assessment battery for measuring EF in two-year-olds. A sample of 2437 children were administered the assessment battery at a mean age of 2;4 years (SD = 0;3 years) in a large-scale field study. Measures of both hot EF (snack and gift delay tasks) and cool EF (six boxes, memory for location, and visual search task) were included. Confirmatory Factor Analyses showed that a two-factor hot and cool EF model fitted the data better than a one-factor model. Measurement invariance was supported across groups differing in age, gender, socioeconomic status (SES), home language, and test setting. Criterion and convergent validity were evaluated by examining relationships between EF and age, gender, SES, home language, and parent and teacher reports of childrens attention and inhibitory control. Predictive validity of the test battery was investigated by regressing childrens pre-academic skills and behavioral problems at age three on the latent hot and cool EF factors at age 2 years. The test battery showed satisfactory psychometric quality and criterion, convergent, and predictive validity. Whereas cool EF predicted both pre-academic skills and behavior problems 1 year later, hot EF predicted behavior problems only. These results show that EF can be assessed with psychometrically sound instruments in children as young as 2 years, and that EF tasks can be reliably applied in large scale field research. The current instruments offer new opportunities for investigating EF in early childhood, and for evaluating interventions targeted at improving EF from a young age.

Individual differences in effects of child care quality : The role of child affective self-regulation and gender

The current study investigated whether the relation between child care quality and childrens socio-emotional behavior depended on childrens affective self-regulation skills and gender. Participants were 545 children (Mage=27 months) from 60 center-based child care centers in the Netherlands. Multi-level analyses showed that children with low affective self-regulation skills or who were male demonstrated less teacher-rated social competence when exposed to relatively low quality child care. In addition, children with low affective self-regulation skills also showed more social competence in the case of relatively high quality child care, suggesting mechanisms of differential susceptibility. No main effects of child care quality or interactions were found for teacher- and parent-rated externalizing behavior. These findings emphasize the importance of considering childrens affective self-regulation skills and gender in understanding the effects of child care quality. High quality child care can be a means to strengthen childrens social development.

Effects of home language environment on inhibitory control in bilingual three-year-old children

Previous studies have shown effects of bilingualism on inhibitory control in preschool children. However, these effects only held for ‘conflict tasks’, and not delay of gratification tasks, and other domains of executive functioning were not investigated. For older children, previous studies have found relationships between bilinguals’ advantages and home language environment. This study investigates effects of bilingualism and bilingual home language environment on executive functioning in three-year-old children. 200 bilingual and 829 monolingual three-year-olds performed tasks of inhibitory control, working memory, and selective attention. Home language environment characteristics were assessed through a parental questionnaire. The bilinguals outperformed the monolinguals on a conflict task only, and this effect was very small. Further analyses showed broader effects on inhibitory control that were related to home language environment: Bilinguals whose parents spoke different languages outperformed bilinguals whose parents spoke the same language on both the conflict task and a delay of gratification task.