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Alun Thomas

Publications and source records attributed to Alun Thomas.

At least 19 recordsLinked to original sources
PubMed2006

Estimating the parameters of a model for protein-protein interaction graphs.

We find accurate approximations for the expected number of three-cycles and unchorded four-cycles under a stochastic distribution for graphs that has been proposed for modelling yeast two-hybrid protein-protein interaction networks. We show that unchorded four-cycles are characteristic motifs under this model and that the count of unchorded four-cycles in the graph is a reliable statistic on which to base parameter estimation. Finally, we test our model against a range of experimental data, obtain parameter estimates from these data and investigate possible improvements in the model. Characterization of this model lays the foundation for its use as a prior distribution in a Bayesian analysis of yeast two-hybrid networks that can potentially aid in identifying false-positive and false-negative results.

Algorithms↗
PubMed2006

Maximum likelihood estimates of allele frequencies and error rates from samples of related individuals by gene counting.

SUMMARY: Graphical modeling is used to extend the gene counting method to compute maximum likelihood estimates of allele frequencies for samples of individuals related in extended pedigrees. Genotypes may be missing or partially observed, and error rates can be simultaneously estimated. AVAILABILITY: The Java classes and Javadocs pages for \mathsf\hbox GeneCountAlleles can be obtained from bioinformatics.med.utah.edu/~alun, which also has more information on its use and file formats.

Biological Evolution↗
PubMed2006

Evidence for linkage on chromosome 3q25-27 in a large autism extended pedigree.

Though autism shows strong evidence for genetic etiology, specific genes have not yet been found. We tested for linkage in a candidate region on chromosome 3q25-27 first identified in Finnish autism families [1]. The peak in this previous study was at D3S3037 (183.9 cM). We tested this region in seven affected family members and 24 of their relatives from a single large extended Utah pedigree of Northern European ancestry. A total of 70 single nucleotide polymorphisms (SNPs) were analyzed from 165 to 204 cM. The maximum NPL-all nonparametric score using SimWalk2snp was 3.53 (empirical p val ue = 0.0003) at 185.2 cM (SNP rs1402229), close to the Finnish peak. A secondary analysis using MCLINK supported this result, with a maximum of 3.92 at 184.6 cM (SNP rs1362645). We tested for alterations in a candidate gene in this region, the fragile X autosomal homolog, FXR1. No variants likely to contribute to autism were found in the coding sequence, exon-intron boundaries, or the promoter region of this gene.

Adolescent↗
PubMed2006

An analysis of unclassified missense substitutions in human BRCA1.

Classification of rare sequence variants observed during mutation screening of susceptibility genes in high-risk individuals presents an interesting and medically important challenge. A recently described method for analysis of unclassified variants in BRCA1 and BRCA2 provides an extensible framework within which several different types of analytic data can be integrated. Among the methods already integrated in this framework are a measure of sequence conservation at specific positions in BRCA1 and BRCA2, and a measure of the difference between wild-type and missense amino acid residues, the Grantham Matrix Score. Recently, we extended the idea of Grantham Matrix Scores to multiple sequence alignments by introducing two new measures, the Grantham variation and Grantham Deviation. We also created a measure of risk associated with sets of BRCA1 missense substitutions, the BRCA1-with-BRCA2 Ascertainment Ratio. Here, we complement these measures with a more powerful measure of risk associated with sets of missense substitutions, the Missense Enrichment Ratio. By combining these four measures, we demonstrate two points: (1) pooled evidence is completely in accord with a hypothesis that missense substitutions that fall at variable positions in the alignment of vertebrate BRCA1s and are within the range of variation observed at those positions are neutral, and (2) many of the missense substitutions falling at invariant positions in the alignment must be deleterious and the longer the period over which the position has been invariant, the stronger the evidence that this is so.

Amino Acid Sequence↗
PubMed2005

Population-based risk assessment for other cancers in relatives of hereditary prostate cancer (HPC) cases.

BACKGROUND: To identify associations of other cancers with hereditary prostate cancer (HPC) we estimated relative risks (RRs) of 36 different cancers in relatives of prostate cancer cases in the Utah Population Data Base (UPDB), which combines genealogical and cancer data for Utah. METHODS: We utilized known genetic relationships between prostate cancer cases and their relatives with cancer, combined with age- and sex-specific cancer rates calculated internally from the UPDB, to estimate RRs for cancer in relatives of prostate cancer cases. RESULTS: Multiple other cancers were observed in excess in both first- and second-degree relatives of HPC cases including colon cancer, non-Hodgkins lymphoma, multiple myeloma, rectal cancer, cancer of the gallbladder, and melanoma (skin). CONCLUSIONS: This analysis supports the existence of heritable prostate cancer syndromes that include other cancers. We hypothesize that the study of homogeneous pedigrees co-segregating prostate cancer and another cancer could allow more straightforward localization and identification of the gene(s) responsible.

Adult↗
PubMed2005

Common polymorphism G(-248)A in the promoter region of the bax gene results in significantly shorter survival in patients with chronic lymphocytic Leukemia once treatment is initiated.

PURPOSE: Chronic lymphocytic leukemia (CLL) is characterized by the development of drug resistance. The underlying biologic and genetic reasons for this resistance are complex, but the bcl-2 gene family seems to play a critical role. This retrospective study assessed the clinical impact of a common single nucleotide polymorphism of the pro-apoptotic bax gene in patients with chronic lymphocytic leukemia. PATIENTS AND METHODS: The frequency of the novel polymorphism, G(-248)A, in the promoter region of the bax gene and bax protein expression was assessed in 203 CLL patients. The results were correlated with clinical outcome. RESULTS: The polymorphism was found in 23% of the CLL cohort and 15% of normal controls with no significant difference in allele frequency between the two groups (P = .15). It was associated with lower Bax protein expression and a shorter overall survival, especially in the treated patient group (P = .03). Furthermore, the adverse impact of the polymorphism was accentuated when comparing survival from the date of first treatment rather than diagnosis (P = .012). No significant difference in age at diagnosis, stage of disease at presentation, lymphocyte doubling time, time to first treatment, or progression-free survival were observed. CONCLUSION: The presence of this single nucleotide polymorphism in CLL critically influences the response to treatment and overall survival. Given the relatively high prevalence of this polymorphism in the normal population, further prospective studies in CLL and other human malignancies are indicated.

Adult↗
PubMed2005

Characterization of linkage disequilibrium structure, mutation history, and tagging SNPs, and their use in association analyses: ELAC2 and familial early-onset prostate cancer.

In association analyses, it is critical that informative single-nucleotide polymorphisms (SNPs) be selected for study and utilized appropriately. We sequenced 38 kb, including exons of ELAC2, promoter region and conserved upstream intergenic sequences. A comprehensive characterization of linkage disequilibrium (LD) structure and mutation history was performed using our principal components analysis (PCA) method and a phylogenetic analysis. We identified a complex pattern of LD structure consistent with the occurrence of both recombination and mutation events within ELAC2. Four overlapping and noncontiguous LD groups were defined. Eight tagging SNPs (tSNPs) were identified, accounting for over 90% of the genetic variation of the 19 total variants. We tested associations between familial early-onset prostate cancer (PRCA) and each variant independently and in haplotypes. We performed these tests using all 19 variants and the 8 tSNPs; the results using tSNP haplotypes accurately represent the association evidence for the full haplotypes. We observed increased evidence for association when SNPs were analyzed in haplotypes. The phylogenetic analysis indicated three haplotypes, clustered farthest from the root-node, all of which were found more often in cases than controls. These three haplotypes together showed the best evidence of association with familial, early-onset PRCA (P=0.0024; odds ratio=2.23; 95% CI, 1.33-3.74), indicating possible allelic heterogeneity. Our results suggest that 8 tSNPs are required to comprehensively assess associations in ELAC2, and that haplotypes should be considered for analysis, and that a knowledge of mutation history may be helpful in parsing allelic heterogeneity and suggesting combinations of haplotypes to be tested.

Aged↗
PubMed2005

Characterizing allelic associations from unphased diploid data by graphical modeling.

A method for estimating a graphical model to describe allelic associations between genetic loci is extended to use diploid genotypes rather than haploid data. It also provides haplotype frequency estimates, estimates of phase for sampled individuals, allows for missing or partial information, genotyping errors, and arbitrary penetrance functions. A data set of 688 unrelated individuals genotyped on 25 genetic loci is used to illustrate haplotype frequency estimation. The frequencies obtained are shown to be similar to those obtained by the PHASE program. We also illustrate how putative loci for traits can be included in the analysis in order to detect allele-phenotype associations. Haplotype reconstruction is illustrated on a standard set of 40 male X-chromosome haplotypes, randomly paired to simulate diploid genotype data. The novel method is shown to be comparable to most existing ones, though the PHASE method does consistently better on this problem. The graphical model approach is shown to have some advantages in terms of tractability and can be used to select informative subsets of loci and to map loci influencing phenotypes.

Alleles↗
PubMed2005

Use of strain typing data to estimate bacterial transmission rates in healthcare settings.

OBJECTIVE: To create an affordable and accurate method for continuously monitoring bacterial transmission rates in healthcare settings. DESIGN: We present a discrete simulation model that relies on the relationship between in-hospital transmission rates and strain diversity. We also present a proof of concept application of this model to a prospective molecular epidemiology data set to estimate transmission rates for Pseudomonas aeruginosa and Staphylococcus aureus. SETTING: Inpatient units of an academic referral center. PATIENTS: All inpatients with nosocomial infections. INTERVENTION: Mathematical model to estimate transmission rates. RESULTS: Maximum likelihood estimates for transmission rates of these two species on different hospital units ranged from 0 to 0.36 transmission event per colonized patient per day. CONCLUSIONS: This approach is feasible, although estimates of transmission rates based solely on strain typed clinical cultures may be too imprecise for routine use in infection control. A modest level of surveillance sampling substantially improves the estimation accuracy.

Bacterial Infections↗
PubMed2004

Graphical modeling of the joint distribution of alleles at associated loci.

Pairwise linkage disequilibrium, haplotype blocks, and recombination hotspots provide only a partial description of the patterns of dependences and independences between the allelic states at proximal loci. On the gross scale, where recombination and spatial relationships dominate, the associations can be reasonably described in these terms. However, on the fine scale of current high-density maps, the mutation process is also important and creates associations between loci that are independent of the physical ordering and that can not be summarized with pairwise measures of association. Graphical modeling provides a standard statistical framework for characterizing precisely these sorts of complex stochastic data. Although graphical models are often used in situations in which assumptions lead naturally to specific models, it is less well known that estimation of graphical models is also a developed field. We show how decomposable graphical models can be fitted to dense genetic data. The objective function is the maximized log likelihood for the model penalized by a multiple of the model's degrees of freedom. We also describe how this can be modified to incorporate prior information of locus position. Simulated annealing is used to find good solutions. Part of the appeal of this approach is that categorical phenotypes can be included in the same analysis and association with polymorphisms can be assessed jointly with the interlocus associations. We illustrate our method with genotypic data from 25 loci in the ELAC2 gene. The results contain third- and fourth-order locus interactions and show that, at this density of markers, linkage disequilibrium is not a simple function of physical distance. Graphical models provide more flexibility to express these features of the joint distribution of alleles than do monotonic functions connecting physical and genetic maps.

Alleles↗
PubMed2004

Natural history of detrusor contractility--minimum ten-year urodynamic follow-up in men with bladder outlet obstruction and those with detrusor.

OBJECTIVE: To check the long-term effect, in male patients, of treated and untreated bladder outlet obstruction (BOO) on detrusor contractility and to explore the relationship between ageing and detrusor underactivity (DUA). MATERIAL AND METHODS: Men investigated at the urodynamic department of Southmead Hospital in Bristol between 1972 and 1986 were traced and three groups were invited for repeat pressure-flow urodynamic studies (PFS). The first two groups included patients over 40 years old, with untreated or surgically treated BOO, and the third group had patients with DUA from all age groups. RESULTS: 196 patients (with a minimum 10 year gap from the first assessment) agreed to have repeat PFS. There was no statistically significant change in bladder contractility index (BCI) in patients with BOO treated by transurethral resection of the prostate (TURP) (mean difference in BCI was 0.01, 95% confidence interval -0.07 to 0.09, n=114). There was also no significant difference in BCI in untreated patients with BOO (p=0.10, n=53). The follow-up BCI was higher in untreated patients than in the surgically treated group. The BCI in patients with DUA did not change significantly after a minimum of 10 years' follow-up. CONCLUSIONS: There is no evidence to suggest that detrusor contractility declines with long-term BOO. Relieving the obstruction surgically does not improve the contractility. This is important when considering and counselling for TURP. Underactive detrusors remain underactive, but do not get worse with time, which could indicate that this is not an ageing process per se and may even have a congenital basis.

Adult↗
PubMed2004

Bryostatin induces protein kinase C modulation, Mcl-1 up-regulation and phosphorylation of Bcl-2 resulting in cellular differentiation and resistance to drug-induced apoptosis in B-cell chronic lymphocytic leukemia cells.

Bryostatin, a macrocyclic lactone and protein kinase C (PKC) modulator, has been shown to have differentiation and anti-tumor activity against several leukemia cell lines in vitro. In this study, we demonstrated Bryostatin-induced differentiation in B-cell chronic lymphocytic leukemia (B-CLL) cells, characterized by an increase in cell size and a marked up-regulation of CD11c expression. The specific inhibitors of the extracellular signal-regulated kinase (ERK) and protein kinase C pathways, PD98059 and GF 109203X respectively, each completely blocked Bryostatin-induced differentiation of B-CLL cells, suggesting that activation of the ERK pathway plays a direct role in this process in a PKC-dependent manner. Furthermore, Bryostatin reduced both spontaneous and drug-induced apoptosis with chlorambucil, fludarabine and 2-chloro-2'-deoxyadenosine (2-Cda) in B-CLL cells. This resistance was associated with an early up-regulation of the anti-apoptotic protein Mcl-1 and post-translational phosphorylation of Bcl-2 at serine 70. The anti-apoptotic effects of Bryostatin were abrogated by GF 109203X, and to a lesser extent by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY294002. Interestingly, the ERK inhibitor, PD98059 inhibited Mcl-1 expression but had little effect on Bryostatin-induced survival suggesting that the ERK pathway predominantly affects differentiation. Taken together these results present an explanation for Bryostatin-induced B-CLL cell survival in which modulation of the PKC pathway couples differentiation with an increase in antiapoptotic protein expression and calls into question the rationale for its use in the treatment of B-CLL.

Apoptosis↗
PubMed2004

Simulating realistic zero loop pedigrees using a bipartite Prufer code and graphical modelling.

Graph algorithms previously developed by the authors are adapted to simulate pedigrees similar to those used in genetic linkage studies which associate disease phenotypes with specific genomic locations. Pedigrees are chosen uniformly at random from the set of those with specified numbers of individuals and matings and which contain no loops. Summary statistics from pedigrees generated in this way can be used to check real pedigrees for anomalies due to biased sampling or phenotypic effects on the pedigree structure.

Algorithms↗
PubMed2003

GCHap: fast MLEs for haplotype frequencies by gene counting.

UNLABELLED: GCHap quickly finds maximum likelihood estimates (MLEs) of frequencies of haplotypes given genotype information on a random sample of individuals. It uses the gene counting method but by excluding haplotypes with zero MLE at an early stage, this implementation uses many orders of magnitude less space and time than naive implementations. A second program, ApproxGCHap, is provided to give alternate estimates for data sets with large numbers of loci or large amounts of missing genotypes. AVAILABILITY: The Java classes and Javadocs pages for GCHap can be obtained from bioinformatics.med.utah.edu/~alun

Algorithms↗
PubMed2003

The P2X7 receptor gene polymorphism 1513 A-->C has no effect on clinical prognostic markers, in vitro sensitivity to fludarabine, Bcl-2 family protein expression or survival in B-cell chronic lymphocytic leukaemia.

A cohort of 121 patients with B-cell chronic lymphocytic leukaemia (B-CLL) was investigated for a single nucleotide polymorphism in the P2X7 receptor gene (1513 A-->C), and the findings were correlated with clinical prognostic markers, in vitro sensitivity to fludarabine, expression of Bcl-2 family proteins and overall survival. The frequency of the polymorphism in B-CLL samples was not significantly different from that found in normal healthy controls (P = 0.27; Fisher's exact test). Furthermore, when the B-CLL patients were analysed according to P2X7 genotype (1513 A/A versus 1513 A/C), there was no significant difference in age at diagnosis, stage at diagnosis, lymphocyte doubling time, time to first treatment, progression-free survival and overall survival, and neither was there any evidence of bias in terms of VH gene mutational status, CD38 expression, in vitro sensitivity to fludarabine or expression of Bcl-2, Bax or Mcl-1 between the two groups. These results indicate that the 1513 A-->C polymorphism of the P2X7 gene is unlikely to play a significant role in the pathogenesis or disease progression of B-CLL.

Aged↗
PubMed2003

Accelerated gene counting for haplotype frequency estimation.

Current implementations of the EM algorithm for estimating haplotype frequencies from genotypes on proximal loci require computational resources that grow as nh2k, where n is the number of individuals genotyped and h is the number of haplotypes possible on k loci. For diallelic loci hk=2k. We present an approach whose computational requirement grows as n2t where t is the largest number of loci at which an individual in the sample is heterozygous. The method is illustrated by haplotype frequency estimation from a sample of 45 individuals genotyped at 26 single nucleotide polymorphisms in the PIK3R1 gene.

1-Phosphatidylinositol 4-Kinase↗
PubMed2003

Flavopiridol induces apoptosis in B-cell chronic lymphocytic leukaemia cells through a p38 and ERK MAP kinase-dependent mechanism.

Flavopiridol, a synthetic flavone, has been previously shown to induce apoptosis in B-cell chronic lymphocytic leukaemia (B-CLL) cells in vitro. The apoptosis was associated with a concomitant activation of caspase-3 without evidence of dependence on functional p53 or Bcl-2 family modulation. In this study, we examined flavopiridol-induced apoptosis in terms of upstream caspase activity, cell cycle distribution and signal transduction, in order to elucidate the mechanism of action of this potent cytotoxic agent. Flavopiridol-induced apoptosis was significantly abrogated by the caspase-9 inhibitor Z-LEHD-FMK (p = 0.002; paired t-test) but was not altered by the caspase-8 inhibitor Z-IETD-FMK (p = 0.37; paired t-test). There was a concentration-dependent increase in a sub G0/G1 peak indicative of apoptotic cells but if these cells were excluded by gating no other cell cycle perturbations were observed suggesting that flavopiridol is capable of inducing apoptosis in cells in all phases of the cell cycle. Significantly, apoptosis was associated with activation of p38 MAP kinase and suppression of ERK activity (p = 0.0036 and p = 0.0048, respectively; paired t-test). These results show for the first time that flavopiridol modulates specific cellular signal transduction pathways in B-CLL cells thereby altering the balance between survival and cell death signals and providing a rationale for the p53-independent nature of flavopiridol-induced apoptosis. Further work is required to identify whether combinations of conventional chemotherapeutic drugs and novel agents like flavopiridol can be used to improve patient outcomes in the treatment of B-CLL.

Antineoplastic Agents↗