Byron F. Robinson

LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition.

To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.

Expressive vocabulary ability of toddlers with Williams syndrome or Down syndrome: a comparison.

School-aged children and adults with Williams syndrome have repeatedly been found to evidence an expressive vocabulary advantage relative to same-aged individuals with Down syndrome. However, Singer Harris, Bellugi, Bates, Jones, and Rossen (1997) argued that this advantage is reversed during the initial period of language acquisition; during this time, children with Down syndrome have larger expressive vocabularies than children with Williams syndrome. This result may have been due to methodological problems, however. This study uses a different design to reconsider the question of whether toddlers with Williams syndrome show an expressive vocabulary advantage over same-aged toddlers with Down syndrome. Parents of twenty-four 2-year-olds with Williams syndrome and twenty-eight 2-year-olds with Down syndrome completed the vocabulary checklist from the MacArthur Communicative Development Inventory: Words and Sentences. The 2 groups were carefully matched for chronological age (CA). Results indicated that the toddlers with Williams syndrome had substantially and significantly larger expressive vocabulary sizes than did the CA-matched children with Down syndrome. Additional analyses of children for whom data were available between the ages of 2 years 0 months and 2 years 3 months indicated that the expressive vocabulary advantage for children with Williams syndrome was present even at this very young age when none of the children had begun to produce word combinations. The Discussion section that follows addresses the discrepancy between these findings and those of Singer Harris et al. and considers the variability present within both the Williams syndrome and Down syndrome samples. Also discussed is the continuity across the lifespan in both the expressive vocabulary advantage shown by individuals with Williams syndrome relative to same-aged individuals with Down syndrome and the expressive vocabulary variability within each syndrome.

Global Spatial Organization by Individuals with Williams Syndrome

Williams syndrome is a genetically determined disorder with a characteristic cognitive profile. Overall IQ tends to be lower than in the normally developing population, performance on measures of linguistic ability is somewhat higher than would be expected given the levels of IQ typical for this group, and there is a particular weakness in visuospatial construction (e.g., block design tasks). A wellknown hypothesis about the deficit in visuospatial construction is that people with Williams syndrome are strongly inclined to be local spatial processors. We report a test of this hypothesis that used a visual search task sensitive to spontaneous global spatial organization. A sample of adults with Williams syndrome produced a pattern of data demonstrating that they spontaneously organize spatial displays at a global level. Indeed, individuals with Williams syndrome found it more difficult to change from global to local processing than participants with normal intelligence. We suggest that the primary problem with visuospatial construction in people with Williams syndrome is not in the salience of single levels of organization but rather in the difficulty of changing between organizations.

A logistic regression based extension of the TDT for continuous and categorical traits.

The transmission disequilibrium test (TDT), designed as a test of linkage in the presence of association (i.e. linkage disequilibrium), has received considerable attention in the recent statistical genetics literature due to its advantages over other within‐family analytic methods. One limitation of the conventional TDT is its application solely to linkage disequilibrium between a genetic marker and a single categorical trait (e.g. presence or absence of a disease). In this paper, we present an extension of the TDT using logistic regression to examine the relation between a candidate gene or genetic marker and one or more continuous or categorical explanatory variables. This logistic regression extension of the TDT possesses all of the desirable features of the conventional TDT, as well as many advantages associated with traditional regression analysis. We describe the model and its properties, as well as a number of its possible applications, and apply it to examine linkage disequilibrium between the dopamine receptor D2 gene (DRD2) and symptoms of childhood attention deficit hyperactivity disorder (ADHD). We also briefly compare the logistic regression TDT to other quantitative TDTs that have been proposed in the literature, and highlight the advantages of a regression‐based approach for examining the relation between a candidate gene and one or more continuous or categorical traits. Given its features, we regard the logistic regression extension of the TDT as a flexible new data analytic method with extensive potential applications to problems in medical, psychiatric, and behavioral genetics.

Linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder: extending the transmission disequilibrium test (TDT) to examine genetic heterogeneity.

Since its introduction into the statistical genetics literature, the transmission disequilibrium test (TDT) has seen widespread use in analyses of linkage and association due not only to its simplicity but also to its desirable properties relative to other within‐family analytic methods. In this paper, we describe an extension to the TDT useful for examining genetic heterogeneity. This extension uses contingency table analyses such as log‐linear analysis to test for differences in linkage disequilibrium across levels of one or more moderator variables. We applied these analyses to test for linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder, as well as for genetic heterogeneity due to sex, diagnostic breadth, and study site. Using data from two studies (the UCSD/UBC and Cardiff data sets), we found evidence suggesting linkage disequilibrium between DAT1 and bipolar disorder, as well as heterogeneity due to diagnostic breadth and study site.

The Roles of Verbal Short-Term Memory and Working Memory in the Acquisition of Grammar by Children With Williams Syndrome

The roles of verbal short-term and working memory were examined in a sample of children with Williams syndrome (mean chronological age 10 years, 2 months) and a sample of grammar-matched children who are developing normally. Forward digit span, nonword repetition, and backward span were all found to be correlated with receptive grammatical ability in the sample of children with Williams syndrome, but not in the sample of children who are developing normally. The relation between working memory, as measured by backward digit span, and grammatical ability was found to be significantly stronger in children with Williams syndrome than in the control group. This finding highlights the possibility that children with Williams syndrome may rely on their working memory to a greater extent than children who are developing normally to learn grammar. Hierarchical regression analyses indicated receptive vocabulary may mediate the relations among forward digit span, backward digit span, and grammatical ability for the children with Williams syndrome. Phonological short-term memory, however, contributed independently to grammatical ability even after receptive vocabulary was taken into account.

Methodological issues in cross-syndrome comparisons: matching procedures, sensitivity (Se), and specificity (Sp).

We are impressed with the magnitude and potential importance of the studies presented by Sigman and Ruskin in this monograph. The within-syndrome findings for the children with autism concerning relations between early joint attention and a range of cognitive abilities a full 9 years later provide the strongest evidence so far that early nonverbal communication skills play an important role in the later development of language, intelligence, and social relations with peers. The purpose of the monograph was not limited to within-syndrome research questions, however. Sigman and Ruskin state that a major goal of the research reported in the monograph was to identify specific, unique, and universal deficits for autism and Down syndrome. They base their method of identifying such syndrome characteristics on the group-matching procedure. Given that this procedure is fraught with difficulties, we are concerned that many of Sigman and Ruskins cross-syndrome comparisons may be incorrect. We do not mean to single out Sigman and Ruskin. The group-matching method is frequently used in special populations research, with the null hypothesis of no differences on the control variable being accepted at dangerously low p values. Our concerns with the group-matching problem extend to much of the extant research that attempts to identify characteristics of individuals based on the performance of their syndrome group relative to a control group. The profiling procedure we outlined seems more fruitful and conceptually satisfying than the traditional matching method. When profiling is not possible, however, it is important to consider the impact of CA confounds and statistical decision procedures used to ensure matching on the control variable, when interpreting syndrome differences on variables of interest.

Testing sequential association: Estimating exact p values using sampled permutations.

Assigning p values to all transitions in a matrix based on their z scores is problematic on 2 counts: The z scores may not be normally distributed, and transitions are interconnected. Permutation tests, which require far fewer assumptions, are an attractive alternative to the standard asymptotic methods for assigning significance. Moreover, when asymptotic z scores are only somewhat above their critical value and sequences are short, often the exact probabilities of permutation tests are not less than .05. Log-linear and permutation methods may be used to winnow the set of transitions initially identified as significant even further. A computer program that performs these tests is available from the authors.

Disentangling early language development : Modeling lexical and grammatical acquisition using an extension of case-study methodology

The early lexical and grammatical development of 1 male child is examined with growth curves and dynamic-systems modeling procedures. Lexical-development described a pattern of logistic growth (R2 = .98). Lexical and plural development shared the following characteristics: Plural growth began only after a threshold was reached in vocabulary size; lexical growth slowed as plural growth increased. As plural use reached full mastery, lexical growth began again to increase. It was hypothesized that a precursor model (P. van Geert, 1991) would fit these data. Subsequent testing indicated that the precursor model, modified to incorporate brief yet intensive plural growth, provided a suitable fit. The value of the modified precursor model for the explication of processes implicated in language development is discussed.

Understanding Log-Linear Analysis with ILOG.

1. Understanding Log‐linear Analysis with ILOG. By R. Bakeman and B. Robinson. ISBN 0 8058 1239 3. Erlbaum, Hillsdale, 1994. 140 pp.