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PubMed2004

Finding haplotype tagging SNPs by use of principal components analysis.

The immense volume and rapid growth of human genomic data, especially single nucleotide polymorphisms (SNPs), present special challenges for both biomedical researchers and automatic algorithms. One such challenge is to select an optimal subset of SNPs, commonly referred as "haplotype tagging SNPs" (htSNPs), to capture most of the haplotype diversity of each haplotype block or gene-specific region. This information-reduction process facilitates cost-effective genotyping and, subsequently, genotype-phenotype association studies. It also has implications for assessing the risk of identifying research subjects on the basis of SNP information deposited in public domain databases. We have investigated methods for selecting htSNPs by use of principal components analysis (PCA). These methods first identify eigenSNPs and then map them to actual SNPs. We evaluated two mapping strategies, greedy discard and varimax rotation, by assessing the ability of the selected htSNPs to reconstruct genotypes of non-htSNPs. We also compared these methods with two other htSNP finders, one of which is PCA based. We applied these methods to three experimental data sets and found that the PCA-based methods tend to select the smallest set of htSNPs to achieve a 90% reconstruction precision.

Chromosome Mapping↗
PubMed2001

Simultaneous modelling of metabolic, genetic and product-interaction networks.

The creation of cell models from annotated genome information, as well as additional data from other databases, requires both a format and medium for its distribution. Standards are described for the representation of the data in the form of Document Type Definitions (DTDs) for XML files. Separate DTDs are detailed for genetic, metabolic and gene product-interaction networks, which can be used to hold information on individual subsystems, or which may be combined to create a whole cell DTD. In the execution of this work, a fifth DTD was also created for a metabolite thesaurus, which allows incorporation of metabolite synonyms and generic nomenclature data into the models. A gene-regulation classification scheme was also created, to facilitate incorporation of gene regulatory information in an efficient manner. The work is described with particular reference to the metabolic network of Escherichia coli, which contains 808 individual enzymes. The assignment of confidence levels to these data, through the use of Gene Ontology evidence codes, is highlighted. In silico investigations may now be performed using the mathematical simulation workbench, DBsolve, which incorporates the facility to introduce data directly from XML.

Computational Biology↗
PubMed1990

Mapping DNA by stochastic relaxation: a new approach to fragment sizes.

Instead of the traditional manipulations with given fixed fragment lengths in the restriction map construction a method of varying the lengths is proposed and realized under the simulated annealing algorithm scheme. The described approach has no upper limit on the number of fragments mapped with even ordinary hardware. A program has been derived from the algorithm combined with the last-squares refinement procedure for both linear and circular maps. The algorithm's ability to pick up missed maps is illustrated and the problem of reducing the number of solutions is discussed.

Algorithms↗
PubMed2004

Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping.

To explore the potential value of recently developed high-density linkage mapping methods in the analysis of complex disease we have regenotyped five nuclear families first studied in the 1996 UK multiple sclerosis linkage genome screen, using Applied Biosystems high-density microsatellite linkage mapping set, the Illumina BeadArray linkage mapping panel (version 3) and the Affymetrix GeneChip Human Mapping 10K array. We found that genotyping success, information extraction and genotyping accuracy were improved with all systems. These improvements were particularly marked with the SNP-based methods (Illumina and Affymetrix), with little difference between these. The extent of additional information extracted is considerable, indicating that reanalysis of existing multiplex families using these newer systems would substantially increase power.

Chromosome Mapping↗
PubMed1991

EEG brain mapping in diagnostic and therapeutic assessment of dementia.

EEG brain mapping has been proven to be a valuable method in diagnostic and therapeutic assessment in dementia trials, because it is a readily available, inexpensive, high time-resolution method for objective and quantitative evaluation of the neurophysiological aspects of dementias. In 111 mildly to moderately demented patients diagnosed according to DSM-III as both degenerative [senile dementia of the Alzheimer type (SDAT)] and vascular [multi-infarct dementia (MID) type], we were interested in showing not only differences between SDAT and MID patients and normal controls but also the relationship between CT scans, EEG maps, clinical ratings and psychometric tests. CT measures included 10 cerebrospinal fluid (CSF) space variables as well as 17 cortical density measures (1.7 mm3 cubes, Hounsfield units). Clinical investigations consisted of the SCAG score/factors, the digit symbol substitution test, the trailmaking test and the digit span forward test. In brain maps, SDAT patients showed slightly to moderately more slow and less alpha and beta activity as well as a slowing of the dominant frequency (DF) and the centroid (C) than did normal controls. These findings were most prominent in parietal and temporal regions. MID patients exhibited markedly augmented delta/theta and attenuated alpha and beta activity and a slowing of the DF and C. These neurophysiological findings suggest a deterioration of vigilance. Differences between SDAT and MID patients were found mostly in measures concerning differences in the maps. Brain maps of correlation coefficients between CT and EEG variables demonstrated: the greater the anterior horn distance, lateral ventricle distance, and Evan's index, as well as the less cortical density, the more delta/theta and the less alpha and beta activity in the EEG. Moreover, the higher the delta/theta, the less alpha and beta activity, the higher the SCAG scores, and the worse the psychometric performance. From the pharmacological point of view, we observed a significant improvement in vigilance after administration of several nootropic drugs both in normal and pathologically aging subjects, which was associated also with improvement of psychopathometric scores. Based on multi-variante analysis of variance (MANOVA)/Hotlelling T2 we observed a drug's effect in different brain regions of MID and SDAT patients. Thus, pharmaco-EEG mapping mediates valuable information regarding if, how, when, in which dosage, and where a nootropic drug acts on its target organ--the aging human brain.

Aged↗
PubMed1984

The role of angiotensin II receptors in vascular regulation.

Plasma-membrane receptors for angiotensin II (AII) have been identified in many AII-responsive tissues involved in the control of blood pressure via direct or indirect actions on vascular contractility. The specific, high-affinity receptors for AII in adrenal zona glomerulosa, vascular smooth muscle, kidney, brain, and anterior pituitary gland exhibit generally similar binding properties. However, the AII receptors in adrenal zona glomerulosa and vascular smooth muscle undergo reciprocal regulatory changes during alterations in sodium intake. These appear to be mediated by changes in circulating AII and are accompanied by parallel changes in sensitivity to AII. The AII receptors in the anterior pituitary gland are located in lactotrophs and corticotrophs and mediate the stimulatory actions of AII upon prolactin and ACTH secretion, acting in conjunction with other hypothalamic regulators. The anterior pituitary receptors are not affected by changes in sodium balance or AII infusion, in contrast to adrenal and vascular AII receptors, but exhibit similar ligand-binding properties to the sites present in other tissues. In the brain, AII receptors are present in several discrete regions and are particularly concentrated in the circumventricular organs. During dehydration, AII receptors are increased in the subfornical organ, but show no significant changes in the other circumventricular organs. The increase in subfornical-organ receptors is analogous to the up-regulation of AII sites in the adrenal cortex during sodium deficiency and may have a potentiating action upon the dipsogenic role of AII during dehydration. Mapping of AII receptors of the brain by topical autoradiography has revealed a highly characteristic pattern of distribution in brain regions concerned with drinking, adrenergic control, blood-pressure regulation, and hypothalamic control of pituitary-hormone secretion. In the rat kidney, AII receptors have been localized in the cortex and medulla by topical autoradiography with 125I-[Sar1]AII. The renal cortical receptors appear to be localized in glomeruli, whereas the AII receptors in the renal medulla are distributed diffusely in medullary tissue and also as localized radiating stripes which correspond to the vasa rectae bundles. The location of the renal receptors for AII in cortical and medullary sites emphasizes the multiplicity of actions of the octapeptide upon the individual compartments of the kidney.

Adrenal Glands↗
PubMed2005

Radiotracer development in psychiatry.

Over the last 20 years a number of radiotracers that target various neurotransmitter systems have been developed for use in imaging studies in psychiatry, but there are many more targets still to be investigated. The development of a radiotracer for clinical positron emission tomography (PET) or single photon emission computed tomography (SPECT) neuroimaging studies can be a complex and lengthy process with few imaging agents successfully progressing into clinical human studies. One of the most challenging aspects in the procedure is the development of a rapid and simple radiosynthesis protocol to obtain the potential radiotracer with adequate specific activity, isolated radiochemical yield and radiochemical purity for human imaging. Once a candidate has been radiolabelled, full characterization of the radiotracer is required before it can be used in clinical human studies. Pre-clinical studies include investigation into the binding distribution, pharmacokinetics, metabolism, toxicology and dosimetry of a radiotracer. There are many points during the development procedure where a potential radiotracer can be rejected. Due to interspecies differences the development of a radiotracer can either go too far with an unsuccessful candidate or can potentially lead to rejection of a candidate too soon. It is only when the radiotracer has been used in humans can we be certain that a radiotracer is a useful imaging agent for clinical research studies. The development of new technologies, such as micro-PET or SPECT can only improve our ability to predict the success of a radiotracer.

Animals↗
PubMed1992

Topographic mapping of single sweep evoked potentials in the brain.

Single trial analysis of brain-evoked potentials via stochastic parametric identification and filtering is here extended to multichannel recordings, leading to the topographic mapping of the brain activity elicited by a single stimulus, instead of the usual averaged mapping. The temporal dynamics of the subsequent sweeps in the protocol of a neurophysiologic experiment can thus be recovered and quantified also on its spatial characteristic.

Brain Mapping↗
PubMed2006

Challenges in drug development for functional gastrointestinal disorders. Part II: visceral pain.

There is a need to have predictive biomarkers to test novel experimental medicines in functional gastrointestinal disorders. The human pharmacodynamic models and biomarkers pertaining to two important conditions are reviewed in a two-part article: functional dyspepsia (part I) and visceral pain (part II). With visceral pain models, the large coefficient of variation in sensation end points in human studies precludes definitive conclusions such as go/no go decisions or dose selection for phase IIb or III studies, unless very large numbers of patients are evaluated in phase IIA pharmacodynamic studies. This renders such pharmacological studies ambitious, or unachievable in a timely fashion. Moreover, the results of tests and clinical trials should be interpreted with greater knowledge of the drug pharmacokinetics, including the influence of CYP metabolism and potential drug interactions. Thus, it is important to identify valid biomarkers of visceral pain for the assessment of treatment response in pharmacodynamic studies. In this second part of a two-part article, we shall discuss the special challenges in developing medications for visceral pain and the general importance of including pharmacokinetic and pharmacogenomic studies in drug development programmes.

Animals↗
PubMed1999

ESCWGA/NASPE/P experts consensus statement: living anatomy of the atrioventricular junctions. A guide to electrophysiologic mapping. Working Group of Arrhythmias of the European Society of Cardiology. North American Society of Pacing and Electrophysiology.

Current nomenclature for the AV junctions derives from a surgically distorted view, placing the valvar rings and the triangle of Koch in a single plane with anteroposterior and right-left lateral coordinates. Within this convention, the aorta is considered to occupy an anterior position, whereas the mouth of the coronary sinus is shown as being posterior. Although this nomenclature has served its purpose for the description and treatment of arrhythmias dependent on accessory pathways and AV nodal reentry, it is less than satisfactory for the description of atrial and ventricular mapping. To correct these deficiencies, a consensus document has been prepared by experts from the Working Group of Arrhythmias of the European Society of Cardiology and from the North American Society of Pacing and Electrophysiology. It proposes a new, anatomically sound, nomenclature that will be applicable to all chambers of the heart. In this report, we discuss its value for description of the AV junctions and establish the principles of this new nomenclature.

Atrioventricular Node↗
PubMed2007

Role of functional MR in determining language dominance in epilepsy and nonepilepsy populations: a Bayesian analysis.

PURPOSE: To determine the role of functional magnetic resonance (MR) imaging in assessing hemispheric language dominance in epilepsy and nonepilepsy populations. MATERIALS AND METHODS: A Bayesian analysis study was performed. The study was based on data from the published literature; thus, institutional review board approval was not required. The literature was reviewed to obtain pretest probabilities and likelihood ratios, which were analyzed to determine the posttest probability of language dominance by using functional MR imaging. Pretest probabilities of different hand dominances in epilepsy and nonepilepsy populations were obtained from the largest studies available in the literature. Likelihood ratios were derived from the sensitivity and specificity of functional MR imaging by using electrocortical stimulation (ECS) and the Wada test as reference standards. RESULTS: Likelihood ratios for functional MR in determining language dominance were 9.3 and 12.3 with ECS and the Wada test as reference standards, respectively. Use of functional MR increased the final posttest probabilities of hemispheric language dominance in epilepsy and nonepilepsy populations. In the nonepilepsy population, regardless of hand dominance, there was very high posttest probability (>or=96%) of a correlation between functional MR hemisphere activation and definite left-hemisphere language dominance. In the epilepsy population with right-hand dominance or ambidexterity, there was very high posttest probability (>or=95%) of a correlation between functional MR hemisphere activation and definite left-hemisphere language dominance. In the left-handed nonepileptic subjects, there was high posttest probability (81%-83%) of a correlation between functional MR hemisphere activation and definite right-hemisphere language dominance. In the left-handed epilepsy population, there was high posttest probability (80%-97%) of a correlation between functional MR hemisphere activation and definite left-hemisphere language dominance. In the epilepsy population with ambidexterity, there was high posttest probability (80%-87%) of correlations between functional MR hemisphere activation and both definite right-hemisphere and bilateral language dominance. CONCLUSION: Use of functional MR increases importantly the posttest probabilities of hemispheric language dominance in multiple subgroups of individuals with and without epilepsy.

Bayes Theorem↗