Biomedical subjects

J T Williams

Publications and source records attributed to J T Williams.

At least 19 recordsLinked to original sources

PubMed2006

Constrained components for the unstable hip following total hip arthroplasty: a literature review.

Patients with chronic instability or late dislocation following total hip arthroplasty often require operative management. Unfortunately, there is an increased risk of recurrent dislocation following revision in these patients. Over the past decade the use of constrained devices for patients with chronic instability has gained increased interest; however, there is a paucity of studies available in the literature regarding the use of these devices. The purpose of this study was to analyze the available literature over the past 15 years, focusing on larger, long-term studies, to obtain recommendations from the respective articles for indications and contraindications for the use of constrained devices. Our review of eight reports included 1,199 hips in 1,148 patients with a total mean follow-up of 51 months (range, 24 to 124 months). The mean rate of dislocation following revision with a constrained liner was 10% and the mean re-operation rate for reasons other than dislocation was 4%. We concluded that constrained liners are an option for patients who have failed management of instability with other implants, those with instability of unclear etiology, those with cognitive problems who are unable to follow dislocation precautions, those with deficient abductors, and elderly or low-demand individuals with well-positioned implants requiring revision.

Arthroplasty, Replacement, Hip↗

PubMed2005

Genotype-by-sex interaction in the regulation of high-density lipoprotein: the Framingham Heart Study.

Low levels of high-density lipoprotein (HDL) are widely documented as a risk factor for cardiovascular disease (CVD). Furthermore, there is marked sexual dimorphism in both HDL levels and the prevalence of CVD. However, the extent to which genetic factors contribute to such dimorphism has been largely unexplored. We examined the evidence for genotype-by-sex effects on HDL in a longitudinal sample of 1562 participants from 330 families in the Framingham Heart Study at three times points corresponding approximately to 1971-1974, 1980-1983, and 1988-1991. Using a variance component method, we conducted a genome scan of HDL at each time point in males and females, separately and combined, and tested for genotype-by-sex interaction at a quantitative trait locus (QTL) at each time point. Consistent findings were noted only for females on chromosome 2 near marker D2S1328, with adjusted LOD scores of 2.6, 2.2, and 2.1 across the three time points, respectively. In males suggestive linkage was detected on chromosome 16 near marker D16S3396 at the second time point and on chromosome 18 near marker D18S851 at the third time point (adjusted LOD = 2.2 and 2.4, respectively). Although the heritability of HDL is similar in males and females, sex appears to exert a substantial effect on the QTL-specific variance of HDL. When genotype-by-sex interactions exist and are not modeled, the power to detect linkage is reduced; thus our results may explain in part the paucity of significant linkage findings for HDL.

Adult↗

PubMed2004

Power of variance component linkage analysis-II. Discrete traits.

We determine the power of variance component linkage analysis in the case of discrete, dichotomous traits analyzed under a classical liability threshold model. For simplicity we consider randomly ascertained samples and an additive model of variation incorporating a qtl, residual additive genetic factors, and individual-specific random environmental effects. We derive an expression for the power of variance component linkage analysis in arbitrary relative pairs, and compare the power of discrete and quantitative trait linkage analysis in the specific case of sibpairs. The predicted sample sizes required in linkage analysis of sibpairs are confirmed by analysis of simulated data. Unlike the affected-sibpair method, the power of discrete trait variance component analysis increases with trait prevalence. The relative efficiency of a discrete trait for linkage analysis increases with population trait prevalence, but does not exceed about 40% and is typically much less.

Analysis of Variance↗

PubMed2003

Roles of alpha1- and alpha2-adrenoceptors in the nucleus raphe magnus in opioid analgesia and opioid abstinence-induced hyperalgesia.

Noradrenaline and alpha-adrenoceptors have been implicated in the modulation of pain in various behavioral conditions. Noradrenergic neurons and synaptic inputs are present in neuronal circuits critical for pain modulation, but their actions on neurons in those circuits and consequently the mechanisms underlying noradrenergic modulation of pain remain unclear. In this study, both recordings in vitro and behavioral analyses in vivo were used to examine cellular and behavioral actions mediated by alpha1- and alpha2-adrenoceptors on neurons in the nucleus raphe magnus. We found that alpha1- and alpha2-receptors were colocalized in the majority of a class of neurons (primary cells) that inhibit spinal pain transmission and are excited during opioid analgesia. Activation of the alpha1-receptor depolarized whereas alpha2-receptor activation hyperpolarized these neurons through a decrease and an increase, respectively, in potassium conductance. Blockade of the excitatory alpha1-receptor or activation of the inhibitory alpha2-receptor significantly attenuated the analgesia induced by local opioid application, suggesting that alpha1-receptor-mediated synaptic inputs in these primary cells contribute to their excitation during opioid analgesia. In the other cell class (secondary cells) that is thought to facilitate spinal nociception and is inhibited by analgesic opioids, only alpha1-receptors were present. Blocking the alpha1-receptor in these cells significantly reduced the hyperalgesia (increased pain) induced by opioid abstinence. Thus, state-dependent activation of alpha1-mediated synaptic inputs onto functionally distinct populations of medullary pain-modulating neurons contributes to opioid-induced analgesia and opioid withdrawal-induced hyperalgesia.

Action Potentials↗

PubMed2003

Evidence for joint action of genes on diabetes status and CVD risk factors in American Indians: the strong heart family study.

OBJECTIVES: Previous research among American Indians of the strong heart family study (SHFS) has demonstrated significant heritabilities for CVD risk factors and implicated diabetes as an important predictor of several of the phenotypes. Moreover, we recently demonstrated that genetic effects on CVD risk factors differed in diabetic and nondiabetic individuals. In this paper, we investigated whether a significant genetic influence on diabetes status could be identified, and whether there is evidence for joint action of genes on diabetes status and related CVD risk factors. METHODS AND RESULTS: Approximately 950 men and women, age 18 or older, in 32 extended families, were examined between 1997 and 1999. We estimated the effects of genes and environmental covariates on diabetes status using a threshold model and a maximum likelihood variance component approach. Diabetes status exhibited a residual heritability of 22% (h2=0.22). We also estimated the genetic and environmental correlations between diabetes susceptibility and eight risk factors for CVD. All eight CVD risk factors displayed significant genetic correlations with diabetes status (BMI (rhoG=0.55), fibrinogen (rhoG=0.40), HDL-C (rhoG=-0.37), ln triglycerides (rhoG=0.65), FAT (rhoG=0.38 ), PAI-1 (rhoG=0.67), SBP (rhoG=0.57), and WHR (rhoG=0.58)). Three of eight traits (HDL-C (rhoE=-0.32), ln triglycerides (rhoE=0.33), and fibrinogen (rhoE=0.20)) displayed significant environmental correlations with diabetes status. CONCLUSIONS: These findings suggest that in the context of a high prevalence of diabetes, still unidentified diabetes genes may play an important role in influencing variation in CVD risk factors.

Adolescent↗

PubMed2003

Novel family-based approaches to genetic risk in thrombosis.

The genetic basis of thrombosis is complex, involving multiple genes and environmental factors. The field of common complex disease genetics has progressed enormously over the past 10 years with the development of powerful new molecular and analytical strategies that enable localization and identification of the causative genetic variants. During the course of these advances, a major paradigmatic change has been taking place that focuses on the genetic analysis of measurable quantitative traits that are correlated with disease risk vs. the previous emphasis on the analysis of the much less informative dichotomous disease trait. Because of their closer proximity to direct gene action, disease-related quantitative phenotypes represent our best chance to identify the underlying quantitative trait loci (QTLs) that influence disease susceptibility. This approach works best when data can be collected on extended families. Unfortunately, family-based designs are still relatively rare in thrombosis/hemostasis studies. In this review, we detail the reasons why the field would benefit from a more vigorous pursuit of modern family-based genetic studies.

Alleles↗

PubMed2002

Effects of cocaine administration on VTA cell activity in response to prefrontal cortex stimulation.

The repeated use of psychostimulants in humans has been associated with progressive enhancement of anxiety, panic attacks, and eventually paranoid psychosis. The appearance of such behaviors has been termed behavioral sensitization, which forms part of the basic pathological mechanisms involved in drug addiction. Psychostimulants act via a circuit involving the ventral tegmental area (VTA), prefrontal cortex (PFC), and nucleus accumbens. The PFC sends glutamatergic projections that activate dopaminergic neurons in the VTA. These projections provide an extremely important excitatory drive necessary for the development of sensitization. The effects of cocaine administration on the response of dopaminergic VTA cells to activation of the PFC have not been reported. Here the effects of acute cocaine administration on VTA cell response to PFC stimulation are examined. Statistical analysis of the changes in spontaneous activity and evoked response revealed a significant decrease in spontaneous activity at 1.0 mg/kg i.v. after cocaine treatment compared to baseline levels. The net effect was an increase in signal-to-noise ratio. Treatment with MK-801 at a dose of 2 mg/kg showed that the excitatory response was, at least partially, NMDA-mediated. Prazosin pretreatment (0.5 mg/kg i.p.) did not prevent a significant decrease in spontaneous activity brought about by cocaine (15 mg/kg, i.p.). Nonetheless, prazosin alone induced a significant decrease in the response to PFC stimulation when compared to baseline. In addition, iontophoretic application of norepinephrine (NE) onto VTA cells revealed that NE potentiated (19.2%), enhanced (26.9%), or suppressed (46.2%) the glutamate-evoked response in VTA cells. The results suggest that a possible role of cocaine in the process of sensitization might be to amplify the PFC-induced excitation at the VTA. Since the iontophoretic release of NE in almost half of the sampled cells produced similar effects to those of cocaine it may suggest a possible NE-mediated mechanism for cocaine actions.

Animals↗

PubMed2002

Additive host genetic factors influence fecal egg excretion rates during Schistosoma mansoni infection in a rural area in Brazil.

This study quantifies the influence of shared household and kinship on egg counts during Schistosoma mansoni infection in a sample from rural Brazil. Detailed genealogic information allowed assignment of 597 individuals to 6 multihousehold pedigrees residing in 145 households. A variance component method was used to partition egg counts into shared household, additive genetic, and individual-specific environmental effects. Host additive genetic effects consistently accounted for a large proportion of the variation in egg counts: 43% in an unadjusted model and 40% in model adjusted for covariates. In a model that examined the confounding of shared household with kinship, additive genetic effects still accounted for 27% of the variation in egg counts and shared household only 12%. The consistently important role for host additive genetic factors on the variation in egg counts points to new ways of modeling and understanding the mechanisms that contribute to trait variation during infection with S. mansoni.

Animals↗

PubMed2001

A RAVE about opioid withdrawal.

Control of trafficking of g protein-linked receptors is thought to be an important regulatory mechanism for receptor signaling. Finn and Whistler test the hypothesis that agonist-induced trafficking of opioid receptors regulates the development of tolerance and dependence. The results show that measures of tolerance and withdrawal to morphine are decreased under conditions where receptors are trafficked through the endocytic/recycling pathway.

Analgesics, Opioid↗

PubMed2001

Genetic analysis of quantitative traits in highly ascertained samples: total serum IgE in families with asthma.

The objective of this study was to compare the effect of an approximate ascertainment correction using proband phenotypes with heuristic corrections based on sample trait means and on published "standard" population values. Data were from the Collaborative Study on the Genetics of Asthma, which comprises 225 families ascertained through sib pairs affected with asthma. In variance component linkage analysis of IgE no lod scores greater than 3.0 were observed, either with or without several attempted corrections for ascertainment. The ascertained nature of the sample may have compromised the power to detect linkage to a quantitative trait (IgE) associated with the focal phenotype (asthma).

Adult↗

PubMed2001

The effect of pedigree complexity on quantitative trait linkage analysis.

Due to the computational difficulties of performing linkage analysis on large complex pedigrees, most investigators resort to simplifying such pedigrees by some ad hoc strategy. In this paper, we suggest an analytical method to compare the power of various pedigree simplification schemes by using the asymptotic distribution of the likelihood-ratio statistic. We applied the method to the large Hutterine pedigree. Our results indicate that the breaking and reduction of inbreeding loops can greatly diminish the power to localize quantitative trait loci. We also present an efficient Monte Carlo method for estimating identity-by-descent allele sharing in large complex pedigrees. This method is used to facilitate a linkage analysis of serum IgE levels in the Hutterites without simplifying the pedigree.

Adult↗

PubMed2001

Power to localize the major gene for disease liability is increased after accounting for the effects of related quantitative phenotypes.

We used the simulated general population data for Genetic Analysis Workshop 12 to test whether power to localize the major gene for liability to disease is increased after accounting for the effects of correlated quantitative phenotypes. We performed the multipoint variance-component linkage analyses for the discrete trait twice: first analysis with age, sex, and EF1 as covariates, and the second analysis with age, sex, EF1, and Q1-Q5 as covariates. Major locus heritability (h2q) (0.80 +/- 0.06) and lod score (6.4) averaged over the number of replicates used are significantly higher in the second analysis compared with the first analysis (h2q = 0.39 +/- 0.12, lod = 2.6). Thus, in the present analysis, power to detect linkage and localize the genes for liability to disease appears to be increased after accounting for the effects of five quantitative traits that are correlated with the liability.

Chromosome Mapping↗

PubMed2001

Does accounting for mitochondrial genetic variation improve the fit of genetic models?

We describe a simple variance component model for estimating the effect of mitochondrial DNA (mtDNA) inheritance on quantitative trait variation. The model is applied to quantitative trait Q5 in the simulated general population data from Genetic Analysis Workshop (GAW) 12. Although the mitochondrial effect on Q5 is small (5.3%) and the power of the method to detect the effect is correspondingly low, analysis over the available population replicates demonstrates that the effect of maternal relatedness can be detected and estimated accurately.

Analysis of Variance↗

PubMed2001

Linkage analysis of quantitative traits in randomly ascertained pedigrees: comparison of penetrance-based and variance component analysis.

Penetrance-based linkage analysis and variance component linkage analysis are two methods that are widely used to localize genes influencing quantitative traits. Using computer programs PAP and SOLAR as representative software implementations, we have conducted an empirical comparison of both methods' power to map quantitative trait loci in extended, randomly ascertained pedigrees, using simulated data. Two-point linkage analyses were conducted on several quantitative traits of different genetic and environmental etiology using both programs, and the lod scores were compared. The two methods appear to have similar power when the underlying quantitative trait locus is diallelic, with one or the other method being slightly more powerful depending on the characteristics of the quantitative trait and the quantitative trait locus. In the case of a multiallelic quantitative trait locus, however, the variance component approach has much greater power. These findings suggest that one should give careful thought to the likely allelic architecture of the quantitative trait to be analyzed when choosing between these two analytical approaches. It may be the case in general that linkage methods which explicitly or implicitly rely on the assumption of a diallelic trait locus fare poorly when this assumption is incorrect.

Chromosome Mapping↗

PubMed2001

The utility of Bayesian model averaging for detecting known oligogenic effects.

In this paper we examine the utility of the Bayesian model averaging approach proposed by Blangero et al. [Genet Epidemiol 17(Suppl. 1):S67-72, 1999] for the detection of known oligogenic effects on quantitative trait 1 (Q1) in the simulated Genetic Analysis Workshop 12 data. The results were consistent with the underlying genetic model: two major QTLs were identified on chromosomes 19 and 2, with heritabilities of 17% and 20%, respectively, located near the position of major genes 1 and 2.

Analysis of Variance↗

PubMed2001

Distribution of lod scores in oligogenic linkage analysis.

In variance component oligogenic linkage analysis it can happen that the residual additive genetic variance bounds to zero when estimating the effect of the ith quantitative trait locus. Using quantitative trait Q1 from the Genetic Analysis Workshop 12 simulated general population data, we compare the observed lod scores from oligogenic linkage analysis with the empirical lod score distribution under a null model of no linkage. We find that zero residual additive genetic variance in the null model alters the usual distribution of the likelihood-ratio statistic.

Chromosome Mapping↗

PubMed2001

Searching for genes underlying normal variation in human adiposity.

A primary challenge in biomedical research today is the elucidation of the underlying genetic architecture of complex conditions such as obesity. In contrast to simple Mendelian disorders that result from a mutation in a single gene, complex phenotypes are the product of the action (as well as interaction) of multiple genes and environmental factors. The genetic configuration of these genes can range from effectively polygenic (i.e., many genes each with a relatively small contribution) to oligogenic (i.e., a few genes with relatively large measurable effects often expressed on a residual additive genetic background). While the task at hand is complicated, it is not intractable; however, it does require consideration of the nature of the disease and definition of its associated phenotypes in selecting the most appropriate study design. Here we will discuss the characteristics of obesity and its related phenotypes, which must be considered in designing analyses to identify the genes involved as well as reviewing what these approaches have provided in the search for genes influencing adiposity in humans

Body Mass Index↗

PubMed2001

Variance component methods for detecting complex trait loci.

Variance component-based linkage analysis has become a major statistical tool for the localization and evaluation of quantitative trait loci influencing complex phenotypes. The variance component approach has many benefits--it can, for example, be used to analyze large pedigrees, and it is able to accommodate multiple loci simultaneously in a true oligogenic model. Important biological phenomena such as genotype-environment interaction and epistasis are also examined easily in a variance component framework. In this chapter, we review the basic statistical features of variance component linkage analysis, with an emphasis on its power and robustness to distributional violations.

Analysis of Variance↗