Biomedical subjects

David J Cutler

Publications and source records attributed to David J Cutler.

11 recordsLinked to original sources

PubMed2025

A powerful framework for differential co-expression analysis of general risk factors.

MOTIVATION: Differential co-expression analysis (DCA) aims to identify genes in a pathway whose shared expression depends on a risk factor. While DCA provides insights into the biological activity of diseases, existing methods are limited to categorical risk factors and/or suffer from bias due to batch and variance-specific effects. We propose a new framework, Kernel-based DCA (KDCA), that harnesses correlation patterns between genes in a pathway to detect differential co-expression arising from general (i.e. continuous, discrete, or categorical) risk factors. RESULTS: Using various simulated pathway architectures, we find that KDCA accounts for common sources of bias to control the type I error rate while substantially increasing the power compared to the standard eigengene approach. We then applied KDCA to The Cancer Genome Atlas thyroid data set and found several differentially co-expressed pathways by age of diagnosis and BRAF mutation status that were undetected by the eigengene method. Collectively, our results demonstrate that KDCA is a powerful testing framework that expands DCA applications in expression studies. AVAILABILITY AND IMPLEMENTATION: KDCA is publicly available in the R package kdca. The package can be downloaded at https://github.com/ajbass/kdca.

Humans↗

PubMed2004

Pharmacokinetic parameter prediction from drug structure using artificial neural networks.

Simple methods for determining the human pharmacokinetics of known and unknown drug-like compounds is a much sought-after goal in the pharmaceutical industry. The current study made use of artificial neural networks (ANNs) for the prediction of clearances, fraction bound to plasma proteins, and volume of distribution of a series of structurally diverse compounds. A number of theoretical descriptors were generated from the drug structures and both automated and manual pruning were used to derive optimal subsets of descriptors for quantitative structure-pharmacokinetic relationship models. Models were trained on one set of compounds and validated with another. Absolute predicted ability was evaluated using a further independent test set of compounds. Correlations for test compounds ranged from 0.855 to 0.992. Predicted values agreed closely with experimental values for total clearance, renal clearance, and volume of distribution, while predictions for protein binding were encouraging. The combination of descriptor generation, ANNs, and the speed and success of this technique compared with conventional methods shows strong potential for use in pharmaceutical product development.

Drug Design↗

PubMed2004

Discrepancies in dbSNP confirmation rates and allele frequency distributions from varying genotyping error rates and patterns.

SUMMARY: Three recent publications have examined the quality and completeness of public database single nucleotide polymorphism (dbSNP) and have come to dramatically different conclusions regarding dbSNPs false positive rate and the proportion of dbSNPs that are expected to be common. These studies employed different genotyping technologies and different protocols in determining minimum acceptable genotyping quality thresholds. Because heterozygous sites typically have lower quality scores than homozygous sites, a higher minimum quality threshold reduces the number of false positive SNPs, but yields fewer heterozygotes and leads to fewer confirmed SNPs. To account for the different confirmation rates and distributions of minor allele frequencies, we propose that the three confirmation studies have different false positive and false negative rates. We developed a mathematical model to predict SNP confirmation rates and the apparent distribution of minor allele frequencies under user-specified false positive and false negative rates. We applied this model to the three published studies and to our own resequencing effort. We conclude that the dbSNP false positive rate is approximately 15-17% and that the reported confirmation studies have vastly different genotyping error rates and patterns.

Algorithms↗

PubMed2004

Tracking the evolution of the SARS coronavirus using high-throughput, high-density resequencing arrays.

Mutations in the SARS-Coronavirus (SARS-CoV) can alter its clinical presentation, and the study of its mutation patterns in human populations can facilitate contact tracing. Here, we describe the development and validation of an oligonucleotide resequencing array for interrogating the entire 30-kb SARS-CoV genome in a rapid, cost-effective fashion. Using this platform, we sequenced SARS-CoV genomes from Vero cell culture isolates of 12 patients and directly from four patient tissues. The sequence obtained from the array is highly reproducible, accurate (>99.99% accuracy) and capable of identifying known and novel variants of SARS-CoV. Notably, we applied this technology to a field specimen of probable SARS and rapidly deduced its infectious source. We demonstrate that array-based resequencing-by-hybridization is a fast, reliable, and economical alternative to capillary sequencing for obtaining SARS-CoV genomic sequence on a population scale, making this an ideal platform for the global monitoring of SARS-CoV and other small-genome pathogens.

Animals↗

PubMed2003

Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.

Bardet-Biedl syndrome (BBS) is a pleiotropic genetic disorder with substantial inter- and intrafamilial variability, that also exhibits remarkable genetic heterogeneity, with seven mapped BBS loci in the human genome. Recent data have demonstrated that BBS may be inherited either as a simple Mendelian recessive or as an oligogenic trait, since mutations at two loci are sometimes required for pathogenesis. This observation suggests that genetic interactions between the different BBS loci may modulate the phenotype, thus contributing to the clinical variability of BBS. We present three families with two mutations in either BBS1 or BBS2, in which some but not all patients carry a third mutation in BBS1, BBS2 or the putative chaperonin BBS6. In each example, the presence of three mutant alleles correlates with a more severe phenotype. For one of the missense alleles, we also demonstrate that the introduction of the mutation in mammalian cells causes a dramatic mislocalization of the protein compared with the wild-type. These data suggest that triallelic mutations are not always necessary for disease manifestation, but might potentiate a phenotype that is caused by two recessive mutations at an independent locus, thus introducing an additional layer of complexity on the genetic modeling of oligogenicity.

Bardet-Biedl Syndrome↗

PubMed2003

Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test.

The transmission/disequilibrium test (TDT), a family-based test of linkage and association, is a popular and intuitive statistical test for studies of complex inheritance, as it is nonparametric and robust to population stratification. We carried out a literature search and located 79 significant TDT-derived associations between a microsatellite marker allele and a disease. Among these, there were 31 (39%) in which the most common allele was found to exhibit distorted transmission to affected offspring, implying that the allele may be associated with either susceptibility to or protection from a disease. In 27 of these 31 studies (87%), the most common allele appeared to be overtransmitted to affected offspring (a risk factor), and, in the remaining 4 studies, the most common allele appeared to be undertransmitted (a protective factor). In a second literature search, we identified 92 case-control studies in which a microsatellite marker allele was found to have significantly different frequencies in case and control groups. Of these, there were 37 instances (40%) in which the most common allele was involved. In 12 of these 37 studies (32%), the most common allele was enriched in cases relative to controls (a risk factor), and, in the remaining 25 studies, the most common allele was enriched in controls (a protective factor). Thus, the most common allele appears to be a risk factor when identified through the TDT, and it appears to be protective when identified through case-control analysis. To understand this phenomenon, we incorporated an error model into the calculation of the TDT statistic. We show that undetected genotyping error can cause apparent transmission distortion at markers with alleles of unequal frequency. We demonstrate that this distortion is in the direction of overtransmission for common alleles. Therefore, we conclude that undetected genotyping errors may be contributing to an inflated false-positive rate among reported TDT-derived associations and that genotyping fidelity must be increased.

Alleles↗

PubMed2003

Mometasone furoate degradation and metabolism in human biological fluids and tissues.

The in vitro metabolic and non-metabolic degradation kinetics of mometasone furoate (MF) was investigated in selected human biological fluids and subcellular fractions of tissues. Qualitative and quantitative differences in transformation profiles of MF were observed among human biological media. Degradation was the major event in plasma and urine with four new degradation products identified; A: 21-chloro-17alpha-hydroxy-16alpha-methyl-9beta,11beta-oxidopregna-1,4-diene-3,20-dione 17-(2-furoate), B: 9alpha,21beta-dichloro-11beta,21alpha-dihydroxy-16alpha-methylpregna-1,4,17,20-tetraen-3-one 21-(2-furoate), C: 21beta-chloro-21alpha-hydroxy-16alpha-methyl-9beta,11beta-oxidopregna-1,4,17,20-tetraen-3-one 21-(2-furoate), and D: 21-chloro-17alpha-hydroxy-16alpha-methyl-9beta,11beta-oxidopregna-1,4-diene-3,20-dione. A, B and C were predominant and D was minor in plasma while A and C were predominant in urine. Hydrolysis of the 17-ester bond of MF was not a major event in plasma. The turnover of MF in plasma was faster than that in phosphate buffers of pH 7.4. Metabolism of MF occurred primarily and rapidly in liver, appreciably in intestine, but negligibly in in vitro lung tissue. While 6beta-hydroxylation was a major metabolic pathway for MF in microsomes of both human liver and intestine, other parallel and subsequent metabolism pathways could also be involved. If these degradation and metabolic products are also formed and active in humans in vivo, both MF and its 'active' products need to be taken into account when determining the systemic bioavailability of MF and in establishing concentration-effect relationships with this drug.

Adult↗

PubMed2003

Selective descriptor pruning for QSAR/QSPR studies using artificial neural networks.

Selection of optimal descriptors in quantitative structure-activity-property relationship (QSAR/QSPR) studies has been a perennial problem. Artificial Neural Networks (ANNs) have been used widely in QSAR/QSPR studies but less widely in descriptor selection. The current study used ANNs to select an optimal set of descriptors using large numbers of input variables. The effects of clean, noisy, and random input descriptors with linear, nonlinear, and periodic data on synthetic and real data QSAR/QSPR sets were examined. The optimal set of descriptors could be determined using a signal-to-noise ratio method. The optimal values for the rho parameter, which relates sample size to network architecture, were found to vary with the type of data. ANNs were able to detect meaningful descriptors in the presence of large numbers of random false descriptors.

Journal Article↗

PubMed2003

Multiple pharmacokinetic parameter prediction for a series of cephalosporins.

The goal of quantitative structure-pharmacokinetic relationship analyses is to develop useful models that can predict one or more pharmacokinetic properties of a particular compound. In the present study, a multiple-output artificial neural network model was constructed to predict human half-life, renal and total body clearance, fraction excreted in urine, volume of distribution, and fraction bound to plasma proteins for a series of cephalosporins. Descriptors generated solely from drug structure were used as inputs for the model, and the six pharmacokinetic parameters were simultaneously predicted as outputs. The final 10 descriptor model contained sufficient information for successful predictions using both internal and external test compounds. Descriptors were found to contribute to individual pharmacokinetic parameters to differing extents, such that descriptor importance was independent of the relationships between pharmacokinetic parameters. This technique provides the advantage of simultaneous prediction of multiple parameters using information obtained by nonexperimental means, with the potential for use during the early stages of drug development.

Cephalosporins↗

PubMed2003

The mouse VPAC2 receptor confers suprachiasmatic nuclei cellular rhythmicity and responsiveness to vasoactive intestinal polypeptide in vitro.

Expression of coherent and rhythmic circadian (approximately 24 h) variation of behaviour, metabolism and other physiological processes in mammals is governed by a dominant biological clock located in the hypothalamic suprachiasmatic nuclei (SCN). Photic entrainment of the SCN circadian clock is mediated, in part, by vasoactive intestinal polypeptide (VIP) acting through the VPAC2 receptor. Here we used mice lacking the VPAC2 receptor (Vipr2-/-) to examine the contribution of this receptor to the electrophysiological actions of VIP on SCN neurons, and to the generation of SCN electrical firing rate rhythms SCN in vitro. Compared with wild-type controls, fewer SCN cells from Vipr2-/- mice responded to VIP and the VPAC2 receptor-selective agonist Ro 25-1553. By contrast, similar proportions of Vipr2-/- and wild-type SCN cells responded to gastrin-releasing peptide, arginine vasopressin or N-methyl-D-aspartate. Moreover, VIP-evoked responses from control SCN neurons were attenuated by the selective VPAC2 receptor antagonist PG 99-465. In firing rate rhythm experiments, the midday peak in activity observed in control SCN cells was lost in Vipr2-/- mice. The loss of electrical activity rhythm in Vipr2-/- mice was mimicked in control SCN slices by chronic treatment with PG 99-465. These results demonstrate that the VPAC2 receptor is necessary for the major part of the electrophysiological actions of VIP on SCN cells in vitro, and is of fundamental importance for the rhythmic and coherent expression of circadian rhythms governed by the SCN clock. These findings suggest a novel role of VPAC2 receptor signalling, and of cell-to-cell communication in general, in the maintenance of core clock function in mammals, impacting on the cellular physiology of SCN neurons.

Animals↗

PubMed2002

Haplotype inference in random population samples.

Contemporary genotyping and sequencing methods do not provide information on linkage phase in diploid organisms. The application of statistical methods to infer and reconstruct linkage phase in samples of diploid sequences is a potentially time- and labor-saving method. The Stephens-Smith-Donnelly (SSD) algorithm is one such method, which incorporates concepts from population genetics theory in a Markov chain-Monte Carlo technique. We applied a modified SSD method, as well as the expectation-maximization and partition-ligation algorithms, to sequence data from eight loci spanning >1 Mb on the human X chromosome. We demonstrate that the accuracy of the modified SSD method is better than that of the other algorithms and is superior in terms of the number of sites that may be processed. Also, we find phase reconstructions by the modified SSD method to be highly accurate over regions with high linkage disequilibrium (LD). If only polymorphisms with a minor allele frequency >0.2 are analyzed and scored according to the fraction of neighbor relations correctly called, reconstructions are 95.2% accurate over entire 100-kb stretches and are 98.6% accurate within blocks of high LD.

Algorithms↗