Biomedical subjects

Thomas S Price

Publications and source records attributed to Thomas S Price.

17 recordsLinked to original sources

PubMed2006

EBP, a program for protein identification using multiple tandem mass spectrometry datasets.

MS/MS combined with database search methods can identify the proteins present in complex mixtures. High throughput methods that infer probable peptide sequences from enzymatically digested protein samples create a challenge in how best to aggregate the evidence for candidate proteins. Typically the results of multiple technical and/or biological replicate experiments must be combined to maximize sensitivity. We present a statistical method for estimating probabilities of protein expression that integrates peptide sequence identifications from multiple search algorithms and replicate experimental runs. The method was applied to create a repository of 797 non-homologous zebrafish (Danio rerio) proteins, at an empirically validated false identification rate under 1%, as a resource for the development of targeted quantitative proteomics assays. We have implemented this statistical method as an analytic module that can be integrated with an existing suite of open-source proteomics software.

Algorithms↗

PubMed2006

Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease.

BACKGROUND AND OBJECTIVE: We performed a placebo-controlled, randomized study to address whether celecoxib or ibuprofen undermines the functional range of inhibition of platelet cyclooxygenase (COX)-1 activity by aspirin in patients with osteoarthritis and stable ischemic heart disease. METHODS: Twenty-four patients who were undergoing long-term treatment with aspirin (100 mg daily) for cardioprotection were coadministered celecoxib, 200 mg twice daily, ibuprofen, 600 mg 3 times daily, or placebo for 7 days. RESULTS: The coadministration of placebo or celecoxib did not undermine the aspirin-related inhibition of platelet COX-1 activity, as assessed by measurements of serum thromboxane B(2) (TXB(2)) levels, as well as platelet function. In contrast, a significant (P < .001) increase in serum TXB(2) level was detected on day 7 before drug administration (median, 19.13 ng/mL [range, 1-47.5 ng/mL]) and at 24 hours after the coadministration of aspirin and ibuprofen (median, 22.28 ng/mL [range, 4.9-44.4 ng/mL]) versus baseline (median, 1.65 ng/mL [range, 0.55-79.8 ng/mL]); this was associated with a significant increase in arachidonic acid-induced platelet aggregation (P < .01) and adenosine diphosphate-induced platelet aggregation (P < .05) and a decrease in the time to form an occlusive thrombus in the platelet function analyzer (P < .01). The urinary excretion of 11-dehydro-TXB(2), an index of systemic thromboxane biosynthesis, was not significantly affected by the coadministration of treatment drugs. At steady state, a comparable and persistent inhibition of lipopolysaccharide-stimulated prostaglandin E(2) generation, a marker of COX-2 activity ex vivo, was caused by ibuprofen (>or=80%) or celecoxib (>or=70%) but not placebo. CONCLUSIONS: Unlike ibuprofen, celecoxib did not interfere with the inhibition of platelet COX-1 activity and function by aspirin despite a comparable suppression of COX-2 ex vivo in patients with osteoarthritis and stable ischemic heart disease.

Adenosine Diphosphate↗

PubMed2006

Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2.

BACKGROUND & AIMS: Variability in response to drugs may influence both efficacy and safety. Cyclooxygenase (COX)-2 inhibitors pose a cardiovascular risk by potentially increasing the likelihood of thrombosis, hypertension, and atherogenesis. Differences between individuals in the response to COX-2 inhibitors would be expected to influence their susceptibility to cardiovascular complications. We examined the variability in degree and selectivity of COX-2 inhibition in humans in response to celecoxib and rofecoxib. METHODS: Fifty healthy volunteers received placebo, rofecoxib (25 mg), and celecoxib (200 mg), randomized by order. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity. A subset of 5 individuals underwent 5 replicate studies to estimate variability in drug response both within and between subjects. RESULTS: Despite the higher COX-2 selectivity of rofecoxib in vitro, the average selectivity attained by 25 mg rofecoxib and 200 mg celecoxib in vivo were not different. However, there was considerable variability at an individual level in the degree of COX-2 inhibition and selectivity attained by both drugs. Approximately one third of the variability was attributable to differences between individuals, suggesting the contribution of genetic sources of variance, such as candidate polymorphisms detected in COX-1 and CYP2C9. CONCLUSIONS: The actual degree of selectivity for inhibition of COX-2 achieved by the coxibs relates both to chemical properties of the drug and to factors within an individual that modulate drug response. These sources of variability might be exploited to identify patients uniquely susceptible to benefit or at developing risk of cardiovascular complications.

Adult↗

PubMed2006

Genetic heterogeneity between the three components of the autism spectrum: a twin study.

OBJECTIVE: This study investigated the etiology of autistic-like traits in the general population and the etiological overlap between the three aspects of the triad of impairments (social impairments, communication impairments, restricted repetitive behaviors and interests) that together define autism spectrum disorders. METHOD: Parents of 3,400 8-year-old twin pairs from the Twins Early Development Study completed the Childhood Asperger Syndrome Test, a screening instrument for autism spectrum symptoms in mainstream samples. Genetic model-fitting of categorical and continuous data is reported. RESULTS: High heritability was found for extreme autistic-like traits (0.64-0.92 for various cutoffs) and autistic-like traits as measured on a continuum (0.78-0.81), with no significant shared environmental influences. All three subscales were highly heritable but showed low covariation. In the genetic modeling, distinct genetic influences were identified for the three components. CONCLUSIONS: These results suggest the triad of impairments that define autism spectrum disorders is heterogeneous genetically. Molecular genetic research examining the three components separately may identify different causal pathways for the three components. The analyses give no indication that different genetic processes affect extreme autistic impairments and autistic impairments as measured on a continuum, but this can only be directly tested once genes are identified.

Asperger Syndrome↗

PubMed2006

Phenotypic and genetic overlap between autistic traits at the extremes of the general population.

OBJECTIVE: To investigate children selected from a community sample for showing extreme autistic-like traits and to assess the degree to which these individual traits--social impairments (SIs), communication impairments (CIs), and restricted repetitive behaviors and interests (RRBIs)--are caused by genes and environments, whether all of them are caused by the same genes and environments, and how often they occur together (as required by an autism diagnosis). METHOD: The most extreme-scoring 5% were selected from 3,419 8-year-old pairs in the Twins Early Development Study assessed on the Childhood Asperger Syndrome Test. Phenotypic associations between extreme traits were compared with associations among the full-scale scores. Genetic associations between extreme traits were quantified using bivariate DeFries-Fulker extremes analysis. RESULTS: Phenotypic relationships between extreme SIs, CIs, and RRBIs were modest. There was a degree of genetic overlap between them, but also substantial genetic specificity. CONCLUSIONS: This first twin study assessing the links between extreme individual autistic-like traits (SIs, CIs, and RRBIs) found that all are highly heritable but show modest phenotypic and genetic overlap. This finding concurs with that of an earlier study from the same cohort that showed that a total autistic symptoms score at the extreme showed high heritability and that SIs, CIs, and RRBIs show weak links in the general population. This new finding has relevance for both clinical models and future molecular genetic studies.

Autistic Disorder↗

PubMed2005

Bioinformatic analysis of circadian gene oscillation in mouse aorta.

BACKGROUND: Circadian rhythmicity of many aspects of cardiovascular function-blood pressure, coagulation and contractile function-is well established, as is diurnal variation in important clinical events, such as myocardial infarction and stroke. Here, we undertake studies to globally assess circadian gene expression in murine aorta. METHODS AND RESULTS: Aortae from mice were harvested at 4-hour intervals for 2 circadian cycles (48 hours). Gene expression was assessed by expression profiling and subjected to a gene ontology bioinformatics analysis. Three hundred thirty transcripts exhibited a circadian pattern of oscillation in mouse aorta, including those intrinsic to the function of the molecular clock. In addition, many genes relevant to protein folding, protein degradation, glucose and lipid metabolism, adipocyte maturation, vascular integrity, and the response to injury are also included in this subset of roughly 7000 genes screened for circadian oscillation. CONCLUSIONS: Detection of functional cassettes of vascular genes that exhibit circadian regulation in the mouse will facilitate elucidation of the mechanisms by which the molecular clock may interact with environmental variables to modulate cardiovascular function and the response to therapeutic interventions.

Animals↗

PubMed2005

SW-ARRAY: a dynamic programming solution for the identification of copy-number changes in genomic DNA using array comparative genome hybridization data.

Comparative genome hybridization (CGH) to DNA microarrays (array CGH) is a technique capable of detecting deletions and duplications in genomes at high resolution. However, array CGH studies of the human genome noting false negative and false positive results using large insert clones as probes have raised important concerns regarding the suitability of this approach for clinical diagnostic applications. Here, we adapt the Smith-Waterman dynamic-programming algorithm to provide a sensitive and robust analytic approach (SW-ARRAY) for detecting copy-number changes in array CGH data. In a blind series of hybridizations to arrays consisting of the entire tiling path for the terminal 2 Mb of human chromosome 16p, the method identified all monosomies between 267 and 1567 kb with a high degree of statistical significance and accurately located the boundaries of deletions in the range 267-1052 kb. The approach is unique in offering both a nonparametric segmentation procedure and a nonparametric test of significance. It is scalable and well-suited to high resolution whole genome array CGH studies that use array probes derived from large insert clones as well as PCR products and oligonucleotides.

Algorithms↗

PubMed2005

Continuity and change in preschool ADHD symptoms: longitudinal genetic analysis with contrast effects.

The genetic and environmental mediation of continuity and change in parent-reported ADHD symptoms were investigated in a cohort of over 6000 twin pairs at 2, 3 and 4 years of age. Genetic analyses of the cross-sectional data yielded heritability estimates of 0.78-0.81 at each age, with contrast effects. A common pathway model provided the best fit to the longitudinal data, indicating that genetic influences underlie 91% of the stable variance in ADHD symptomatology. In other words, what is stable for ADHD symptoms is largely genetic. Contrast effects acting in the same direction at different ages contributed to the observed continuity:longitudinal correlations were greater for dizygotic than monozygotic twins.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

The limits of child effects: evidence for genetically mediated child effects on corporal punishment but not on physical maltreatment.

Research on child effects has demonstrated that children's difficult and coercive behavior provokes harsh discipline from adults. Using a genetically sensitive design, the authors tested the limits of child effects on adult behavior that ranged from the normative (corporal punishment) to the nonnormative (physical maltreatment). The sample was a 1994-1995 nationally representative birth cohort of 1,116 twins and their families who participated in the Environmental Risk Longitudinal Study. Results showed that environmental factors accounted for most of the variation in corporal punishment and physical maltreatment. However, corporal punishment was genetically mediated in part, and the genetic factors that influenced corporal punishment were largely the same as those that influenced children's antisocial behavior, suggesting a child effect. The authors conclude that risk factors for maltreatment are less likely to reside within the child and more likely to reside in characteristics that differ between families.

Adolescent↗

PubMed2004

Genetic and environmental influence on language impairment in 4-year-old same-sex and opposite-sex twins.

BACKGROUND: We investigated the aetiology of language impairment in 579 four-year-old twins with low language performance and their co-twins, members of 160 MZ twin pairs, 131 same-sex DZ pairs and 102 opposite-sex DZ pairs. METHODS: Language impairment in 4-year-olds was defined by scores below the 15th percentile on a general factor derived from an extensive language test battery. Language impairment of different degrees of severity was investigated by using multiple cut-offs below the 15th percentile. RESULTS: DeFries-Fulker extremes analysis indicated that language impairment as measured by the general language scale is under strong genetic influence. In addition, group differences heritability showed an increasing trend (from 38% to 76%) as a function of severity of language impairment. Although more boys are impaired than girls, incorporating opposite-sex DZ pairs into the analysis found neither quantitative nor qualitative differences between boys and girls in genetic and environmental aetiologies. CONCLUSIONS: Language impairment at four years is heritable. This finding replicates previous research on language impairment and extends it by showing that language impairment is heritable in twins selected from a representative community sample. Despite the mean difference between boys and girls, genetic and environmental influences are quantitatively and qualitatively similar for language impairment for boys and girls. For both boys and girls, heritability appears to be greater for more severe language impairment, indicating stronger influence of genes at the lower end of language ability.

Child, Preschool↗

PubMed2004

A longitudinal genetic analysis of low verbal and nonverbal cognitive abilities in early childhood.

By middle childhood, the same genetic factors are largely responsible for individual differences in verbal and nonverbal abilities, suggesting a genetic basis for general cognitive ability ("g"). Our previous work on verbal and nonverbal abilities throughout the normal range of variation during infancy and early childhood suggests that genetic influences show domain-specific as well as domain-general effects, implying that the switch to nearly complete domain-general effects occurs later in development. Much less is known about the genetic structure of low cognitive performance, although our previous work has shown that a composite measure of low "g" is highly heritable at 2, 3 and 4 years of age. We report the first multivariate, longitudinal analyses of low verbal and nonverbal cognitive abilities (defined as the lowest 10% of the distribution) at 2, 3 and 4 years of age using data from 9026 pairs of UK twins assessed by their parents as part of the Twins Early Development Study (TEDS). Domain-general genetic influences increased significantly from 2 to 3 to 4 years. Although the phenotypic polychoric correlation between low verbal and low nonverbal ability was similar at 2, 3 and 4 years (.36,.43,.35), the genetic contribution to the phenotypic correlation increased dramatically (.37,.47,.76), with a corresponding decrease in the comorbid influence of shared environment (.61,.44,.35). We conclude that for low ability, as well as for normal variation in ability, genetic "g" emerges during early childhood but is not fully developed until middle childhood.

Child, Preschool↗

PubMed2003

Outcomes of early language delay: I. Predicting persistent and transient language difficulties at 3 and 4 years.

Parent-based assessments of vocabulary, grammar, nonverbal ability, and use of language to refer to post and future (displaced reference) were obtained for 8,386 twin children at 2 years of age. Children with 2 year vocabulary scores below the 10th centile were designated the early language delay (ELD) group, and their outcomes at 3 and 4 years were contrasted with the remainder of the sample, the typical language (TL) group. At 3 and 4 years old, children were designated as language impaired if their scores fell below the 15th centile on at least 2 of the 3 parent-provided language measures: vocabulary, grammar, and use of abstract language. At 3 years, 44.1% of the ELD group (as compared to 7.2% of the TL group) met criteria for persistent language difficulties, decreasing slightly to 40.2% at 4 years (as compared to 8.5% of the TL group), consistent with previous reports of frequent spontaneous resolution of delayed language in preschoolers. Although relations between language and nonverbal abilities at 2 years and outcome at 3 and 4 years within the ELD group were highly statistically significant, effect sizes were small, and classification of outcome on the basis of data on 2-year-olds was far too inaccurate to be clinically useful. Children whose language difficulties persisted were not necessarily those with the most severe initial difficulties. Furthermore, measures of parental education and the child's history of ear infections failed to substantially improve the prediction.

Child, Preschool↗

PubMed2003

Outcomes of early language delay: II. Etiology of transient and persistent language difficulties.

Genes are known to play an important role in causing specific language impairment, but it is unclear how far a similar etiology is implicated in transient language delay in early childhood. Two-year-old children with vocabulary scores below the 10th centile were selected from a cohort of over 2,800 same-sex twin pairs whose language was assessed by parental report at 2, 3, and 4 years of age. These children with early language delay (ELD) were divided into cases of transient and persistent language difficulties on the basis of outcome at 3 and 4 years. A DeFries-Fulker analysis (J. C. DeFries & D. W. Fulker, 1985) was used to compute group heritability (h2g) of 2-year vocabulary delay separately for those with transient and persistent difficulties. When 3-year and 4-year language attainments were used to categorize outcomes, h2g was similar and modest (.25 or less) for both transient and persistent difficulties. However, when persistent difficulties were defined according to whether parents expressed concern about language at 3 years or according to whether a professional had been consulted about language difficulties at 4 years, heritability was significantly higher. For 289 children with no professional involvement at 4 years, heritability of 2-year vocabulary delay was close to zero, whereas for 134 children with professional involvement, a significant h2g of .41 (SE = .127) was found. Early language delay appears largely environmental in origin for 2-year-olds whose parents do not go on to seek professional help.

Child, Preschool↗

PubMed2003

Genetic and environmental mediation of the relationship between language and nonverbal impairment in 4-year-old twins.

This study of 4-year-old twins investigated the genetic and environmental origins of comorbidity between language impairment and nonverbal ability by testing the extent to which language impairment in one twin predicted nonverbal ability in the co-twin. Impairment of language ability was defined as scores below the 15th percentile on a general language scale derived from a battery of diverse language tests. Four hundred thirty-six children, members of 160 monozygotic (MZ) and 131 same-sex dizygotic (DZ) twin pairs, were identified as language impaired. Language-impaired probands also suffered significant impairments in nonverbal ability. DeFries-Fulker extremes analysis showed evidence for substantial genetic mediation of the phenotypic relationship between language impairment and poor nonverbal ability in that language problems in one twin predicted poor nonverbal ability in the co-twin, much more so for MZ twins than for DZ twins. This finding held even when we excluded those children with language impairment whose nonverbal score indicated general cognitive delay. These results point to a general genetic factor that includes both language and nonverbal problems.

Case-Control Studies↗

PubMed2002

The structure of language abilities at 4 years: a twin study.

Normal language development was studied in 310 pairs of 4-year-old twins born in the United Kingdom in 1994. Twins were assessed individually in their homes on a diverse battery of language and nonverbal measures. Rotated factor analyses indicated the presence of a general Language factor (L) as well as a general Nonverbal (NV) factor. Moderate genetic influence was found for both L and NV abilities. Bivariate genetic analysis estimated a genetic correlation of .63 between L and NV abilities, implying that over half of the genetic influence on L overlaps with genetic influence on NV. These results suggest that at age 4, genetic influences on individual differences in language overlap substantially with genetic influences on individual differences in other cognitive abilities, although perhaps less so than later in development.

Child Language↗

PubMed2002

Associations between behaviour problems and verbal and nonverbal cognitive abilities and disabilities in early childhood.

BACKGROUND: We investigated associations between behaviour problems and verbal and nonverbal cognitive abilities at 2, 3 and 4 years of age both for the entire distribution and for the lowest 5% and 10% of the verbal and nonverbal cognitive disabilities. METHODS: A community sample of 4,000 pairs of twins born in England and Wales in 1994 and 1995 was assessed by their parents at 2, 3 and 4 years using the Revised Rutter Parent Scale for Preschool Children (RRPSPC, behaviour problems), the MacArthur Communicative Development Inventory (MCDI, verbal development), and the Parent Report of Children's Abilities (PARCA, nonverbal cognitive development). RESULTS: For the entire sample, behaviour problem scores were modestly associated with lower MCDI and PARCA scores - correlations were less than .30. Similarly modest effect sizes were found for relationships between behaviour problem scores and the lowest 5% and 10% of the MCDI and of the PARCA distributions. Associations were stronger for nonverbal than for verbal development, increased from 2 to 3 to 4 years, and, at the extremes of the distributions, were stronger for boys than for girls. Multivariate genetic analyses indicated that both genetic and shared environmental factors mediate the links between behaviour problems and cognitive development both for the total distribution and for the extremes. Genetic links may be stronger for the extremes than for the total sample. CONCLUSIONS: We conclude that, in this community sample of young children, associations between behaviour problems and verbal and nonverbal cognitive development are generally modest for the entire distribution and are no greater at the extremes than expected on the basis of the associations for the entire distribution.

Aptitude Tests↗

PubMedDate not supplied

The genetic and environmental origins of language disability and ability.

This study investigated whether genes affect language impairment to the same extent as they affect differences in language ability following up an earlier study of 579 four-year-old twins with low language performance and their cotwins (Viding et al., in press). The present study selected low-language twins from 6,963 pairs of twins from the Twins Early Development Study assessed for vocabulary and grammar by their parents at 2, 3, and 4 years of age. For impaired groups corresponding to the lowest scoring 5% and 10% at each age, twin concordances and model-fitting analyses indicated substantial genetic influence on the mean difference between affected children and the population (h2g), generally higher than for individual differences for the entire sample (h2).

Child, Preschool↗