Sophie van der Sluis

Working Memory in Dutch Children with Reading- and Arithmetic-Related LD

The aim of the two studies presented in this article was to examine working memory performance in Dutch children with various subtypes of learning disabilities. The performance of children with reading disabilities (RD) was compared to that of children with arithmetic disabilities (AD), children with both reading and arithmetic disabilities (RAD), and chronological age-matched controls (CA). Measures covered the phonological loop, the visuospatial sketchpad, and the central executive. In both studies, the children with RD showed no working memory deficits whatsoever. Children with AD showed a single impairment on the task tapping working memory for dynamic visual information. Children with RAD performed lower only on the digit span backward task. The failure to replicate the expected working memory deficits in children with reading-related disabilities is discussed.The aim of the two studies presented in this article was to examine working memory performance in Dutch children with various subtypes of learning disabilities. The performance of children with reading disabilities (RD) was compared to that of children with arithmetic disabilities (AD), children with both reading and arithmetic disabilities (RAD), and chronological age—matched controls (CA). Measures covered the phonological loop, the visuospatial sketchpad, and the central executive. In both studies, the children with RD showed no working memory deficits whatsoever. Children with AD showed a single impairment on the task tapping working memory for dynamic visual information. Children with RAD performed lower only on the digit span backward task. The failure to replicate the expected working memory deficits in children with reading-related disabilities is discussed.

Dimensions of Normal Personality as Networks in Search of Equilibrium: You Can't Like Parties if You Don't Like People

In one currently dominant view on personality, personality dimensions (e.g. extraversion) are causes of human behaviour, and personality inventory items (e.g. ‘I like to go to parties’ and ‘I like people’) are measurements of these dimensions. In this view, responses to extraversion items correlate because they measure the same latent dimension. In this paper, we challenge this way of thinking and offer an alternative perspective on personality as a system of connected affective, cognitive and behavioural components. We hypothesize that these components do not hang together because they measure the same underlying dimension; they do so because they depend on one another directly for causal, homeostatic or logical reasons (e.g. if one does not like people and it is harder to enjoy parties). From this ‘network perspective’, personality dimensions emerge out of the connectivity structure that exists between the various components of personality. After outlining the network theory, we illustrate how it applies to personality research in four domains: (i) the overall organization of personality components; (ii) the distinction between state and trait; (iii) the genetic architecture of personality; and (iv) the relation between personality and psychopathology. Copyright

The Construction and Validation of an Abridged Version of the Autism-Spectrum Quotient (AQ-Short).

This study reports on the development and validation of an abridged version of the 50-item Autism-Spectrum Quotient (AQ), a self-report measure of autistic traits. We aimed to reduce the number of items whilst retaining high validity and a meaningful factor structure. The item reduction procedure was performed on data from 1,263 Dutch students and general population adults. The resulting 28-item AQ-Short was subsequently validated in 3 independent samples, both clinical and controls, from the Netherlands and the UK. The AQ-Short comprises two higher-order factors assessing ‘social behavioral difficulties’ and ‘a fascination for numbers/patterns’. The clear factor structure of the AQ-Short and its high sensitivity and specificity make the AQ-Short a useful alternative to the full 50-item version.

TATES: efficient multivariate genotype-phenotype analysis for genome-wide association studies.

To date, the genome-wide association study (GWAS) is the primary tool to identify genetic variants that cause phenotypic variation. As GWAS analyses are generally univariate in nature, multivariate phenotypic information is usually reduced to a single composite score. This practice often results in loss of statistical power to detect causal variants. Multivariate genotype–phenotype methods do exist but attain maximal power only in special circumstances. Here, we present a new multivariate method that we refer to as TATES (Trait-based Association Test that uses Extended Simes procedure), inspired by the GATES procedure proposed by Li et al (2011). For each component of a multivariate trait, TATES combines p-values obtained in standard univariate GWAS to acquire one trait-based p-value, while correcting for correlations between components. Extensive simulations, probing a wide variety of genotype–phenotype models, show that TATESs false positive rate is correct, and that TATESs statistical power to detect causal variants explaining 0.5% of the variance can be 2.5–9 times higher than the power of univariate tests based on composite scores and 1.5–2 times higher than the power of the standard MANOVA. Unlike other multivariate methods, TATES detects both genetic variants that are common to multiple phenotypes and genetic variants that are specific to a single phenotype, i.e. TATES provides a more complete view of the genetic architecture of complex traits. As the actual causal genotype–phenotype model is usually unknown and probably phenotypically and genetically complex, TATES, available as an open source program, constitutes a powerful new multivariate strategy that allows researchers to identify novel causal variants, while the complexity of traits is no longer a limiting factor.

Phenotypic complexity, measurement bias, and poor phenotypic resolution contribute to the missing heritability problem in genetic association studies.

Background The variance explained by genetic variants as identified in (genome-wide) genetic association studies is typically small compared to family-based heritability estimates. Explanations of this ‘missing heritability’ have been mainly genetic, such as genetic heterogeneity and complex (epi-)genetic mechanisms. Methodology We used comprehensive simulation studies to show that three phenotypic measurement issues also provide viable explanations of the missing heritability: phenotypic complexity, measurement bias, and phenotypic resolution. We identify the circumstances in which the use of phenotypic sum-scores and the presence of measurement bias lower the power to detect genetic variants. In addition, we show how the differential resolution of psychometric instruments (i.e., whether the instrument includes items that resolve individual differences in the normal range or in the clinical range of a phenotype) affects the power to detect genetic variants. Conclusion We conclude that careful phenotypic data modelling can improve the genetic signal, and thus the statistical power to identify genetic variants by 20–99%.

A Note on False Positives and Power in G × E Modelling of Twin Data

The variance components models for gene–environment interaction proposed by Purcell in 2002 are widely used. In both the bivariate and the univariate parameterization of these models, the variance decomposition of trait T is a function of moderator M. We show that if M and T are correlated, and moderator M is correlated between twins as well, the univariate parameterization produces a considerable increase in false positive moderation effects. A simple extension of this univariate moderation model prevents this elevation of the false positive rate provided the covariance between M and T is itself not also subject to moderation. If the covariance between M and T varies as a function of M, then moderation effects observed in the univariate setting should be interpreted with care as these can have their origin in either moderation of the covariance between M and T or in moderation of the unique paths of T. We conclude that researchers should use the full bivariate moderation model to study the presence of moderation on the covariance between M and T. If such moderation can be ruled out, subsequent use of the extended univariate moderation model, as proposed in this paper, is recommended as this model is more powerful than the full bivariate moderation model.

The Amsterdam resting-state questionnaire reveals multiple phenotypes of resting-state cognition.

Resting-state neuroimaging is a dominant paradigm for studying brain function in health and disease. It is attractive for clinical research because of its simplicity for patients, straightforward standardization, and sensitivity to brain disorders. Importantly, non-sensory experiences like mind wandering may arise from ongoing brain activity. However, little is known about the link between ongoing brain activity and cognition, as phenotypes of resting-state cognition—and tools to quantify them—have been lacking. To facilitate rapid and structured measurements of resting-state cognition we developed a 50-item self-report survey, the Amsterdam Resting-State Questionnaire (ARSQ). Based on ARSQ data from 813 participants assessed after 5 min eyes-closed rest in their home, we identified seven dimensions of resting-state cognition using factor analysis: Discontinuity of Mind, Theory of Mind, Self, Planning, Sleepiness, Comfort, and Somatic Awareness. Further, we showed that the structure of cognition was similar during resting-state fMRI and EEG, and that the test-retest correlations were remarkably high for all dimensions. To explore whether inter-individual variation of resting-state cognition is related to health status, we correlated ARSQ-derived factor scores with psychometric scales measuring depression, anxiety, and sleep quality. Mental health correlated positively with Comfort and negatively with Discontinuity of Mind. Finally, we show that sleepiness may partially explain a resting-state EEG profile previously associated with Alzheimers disease. These findings indicate that the ARSQ readily provides information about cognitive phenotypes and that it is a promising tool for research on the neural correlates of resting-state cognition in health and disease.

Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex

The size and shape of dendrites and axons are strong determinants of neuronal information processing. Our knowledge on neuronal structure and function is primarily based on brains of laboratory animals. Whether it translates to human is not known since quantitative data on “full” human neuronal morphologies are lacking. Here, we obtained human brain tissue during resection surgery and reconstructed basal and apical dendrites and axons of individual neurons across all cortical layers in temporal cortex (Brodmann area 21). Importantly, morphologies did not correlate to etiology, disease severity, or disease duration. Next, we show that human L(ayer) 2 and L3 pyramidal neurons have 3-fold larger dendritic length and increased branch complexity with longer segments compared with temporal cortex neurons from macaque and mouse. Unsupervised cluster analysis classified 88% of human L2 and L3 neurons into human-specific clusters distinct from mouse and macaque neurons. Computational modeling of passive electrical properties to assess the functional impact of large dendrites indicates stronger signal attenuation of electrical inputs compared with mouse. We thus provide a quantitative analysis of “full” human neuron morphologies and present direct evidence that human neurons are not “scaled-up” versions of rodent or macaque neurons, but have unique structural and functional properties.

Sheltering behavior and locomotor activity in 11 genetically diverse common inbred mouse strains using home-cage monitoring.

Functional genetic analyses in mice rely on efficient and in-depth characterization of the behavioral spectrum. Automated home-cage observation can provide a systematic and efficient screening method to detect unexplored, novel behavioral phenotypes. Here, we analyzed high-throughput automated home-cage data using existing and novel concepts, to detect a plethora of genetic differences in spontaneous behavior in a panel of commonly used inbred strains (129S1/SvImJ, A/J, C3H/HeJ, C57BL/6J, BALB/cJ, DBA/2J, NOD/LtJ, FVB/NJ, WSB/EiJ, PWK/PhJ and CAST/EiJ). Continuous video-tracking observations of sheltering behavior and locomotor activity were segmented into distinguishable behavioral elements, and studied at different time scales, yielding a set of 115 behavioral parameters of which 105 showed highly significant strain differences. This set of 115 parameters was highly dimensional; principal component analysis identified 26 orthogonal components with eigenvalues above one. Especially novel parameters of sheltering behavior and parameters describing aspects of motion of the mouse in the home-cage showed high genetic effect sizes. Multi-day habituation curves and patterns of behavior surrounding dark/light phase transitions showed striking strain differences, albeit with lower genetic effect sizes. This spontaneous home-cage behavior study demonstrates high dimensionality, with a strong genetic contribution to specific sets of behavioral measures. Importantly, spontaneous home-cage behavior analysis detects genetic effects that cannot be studied in conventional behavioral tests, showing that the inclusion of a few days of undisturbed, labor extensive home-cage assessment may greatly aid gene function analyses and drug target discovery.

A Note on Testing Perfect Correlations in SEM

This article is concerned with the seemingly simple problem of testing whether latent factors are perfectly correlated (i.e., statistically indistinct). In recent literature, researchers have used different approaches, which are not always correct or complete. We discuss the parameter constraints required to obtain such perfectly correlated latent factors in the context of 4 commonly used models: (a) the oblique factor model, (b) the hierarchical factor model, (c) models in which the factors are predicted by a covariate, and (d) models in which the factors are predictors of a dependent variable. It is shown that the necessary constraints depend on the choice of scaling. We illustrate testing the indistinctiveness of factors with 2 real data examples.