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PubMed2000

Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design.

In the 20th century geneticists began to unravel some of the simpler aspects of the etiology of inherited diseases in humans. The theory of linkage analysis was developed and applied long before the advent of molecular biology, but only the technological advances of the second half of the 20th century made large-scale gene mapping with a dense genome-spanning set of markers a reality. More recently, the primary topic of interest has shifted from simple Mendelian diseases, for which genotypes of some gene are the cause of disease, to more complex diseases, for which genotypes of some set of genes together with environmental factors merely alter the probability that an individual gets the disease, although individual factors are typically insufficient to cause the disease outright. To this end, a great deal of dogma has evolved about the best way to skin this cat, although to date success has been minimal with any approach. We postulate that the main reason for this is a lack of attention to experimental design. Once the data have been ascertained, the most powerful statistical methods will not be able to salvage an inappropriately designed study (Andersen 1990). Each phenotype and/or population mandates its own individually tailored study design to maximize the chances of successful gene mapping. We suggest that careful consideration of the available data from real genotype-phenotype correlation studies (as opposed to oversimplified theoretically tractable models), and the practical feasibility of different ascertainment schemes dictate how one should proceed. In this review we review the theory and practice of gene mapping at the close of the 20th century, showing that most methods of linkage and linkage disequilibrium analysis are similar in a fundamental sense, with the differences being related more to study design and ascertainment than to technical details of the underlying statistical analysis. To this end, we propose a new focus in the field of statistical genetics that more explicitly highlights the primacy of study design as the means to increase power for gene mapping.

Algorithms↗
PubMed1993

Recent advances in surgery of the temporal bone and skull base.

Remarkable advances have been made in the field of neuro-otologic and skull base surgery within the past decade. Each component of the "disease model"--prevention, diagnosis, therapy, and rehabilitation--is undergoing rapid progress. The purpose of this paper is to highlight only a few of these achievements. Each topic chosen has witnessed recent advancement in one aspect of the disease model. Neurofibromatosis (prevention) has been subjected to chromosomal mapping, allowing for genetic counseling. Intraoperative facial nerve monitoring (diagnosis) has allowed improved anatomic and functional preservation of this nerve during surgery. Embolization of glomus tumors (therapy) has rendered these difficult lesions more surgically manageable, and cochlear implantation (rehabilitation) has allowed the profoundly deaf to play a more active role in society. Each of these topics is briefly discussed as it relates to the temporal bone surgeon.

Cochlear Implants↗
PubMed2006

Mapping anatomical correlations across cerebral cortex (MACACC) using cortical thickness from MRI.

We introduce MACACC-Mapping Anatomical Correlations Across Cerebral Cortex-to study correlated changes within and across different cortical networks. The principal topic of investigation is whether the thickness of one area of the cortex changes in a statistically correlated fashion with changes in thickness of other cortical regions. We further extend these methods by introducing techniques to test whether different population groupings exhibit significantly varying MACACC patterns. The methods are described in detail and applied to a normal childhood development population (n = 292), and show that association cortices have the highest correlation strengths. Taking Brodmann Area (BA) 44 as a seed region revealed MACACC patterns strikingly similar to tractography maps obtained from diffusion tensor imaging. Furthermore, the MACACC map of BA 44 changed with age, older subjects featuring tighter correlations with BA 44 in the anterior portions of the superior temporal gyri. Lastly, IQ-dependent MACACC differences were investigated, revealing steeper correlations between BA 44 and multiple frontal and parietal regions for the higher IQ group, most significantly (t = 4.0) in the anterior cingulate.

Adolescent↗
PubMed2005

ALE meta-analysis: controlling the false discovery rate and performing statistical contrasts.

Activation likelihood estimation (ALE) has greatly advanced voxel-based meta-analysis research in the field of functional neuroimaging. We present two improvements to the ALE method. First, we evaluate the feasibility of two techniques for correcting for multiple comparisons: the single threshold test and a procedure that controls the false discovery rate (FDR). To test these techniques, foci from four different topics within the literature were analyzed: overt speech in stuttering subjects, the color-word Stroop task, picture-naming tasks, and painful stimulation. In addition, the performance of each thresholding method was tested on randomly generated foci. We found that the FDR method more effectively controls the rate of false positives in meta-analyses of small or large numbers of foci. Second, we propose a technique for making statistical comparisons of ALE meta-analyses and investigate its efficacy on different groups of foci divided by task or response type and random groups of similarly obtained foci. We then give an example of how comparisons of this sort may lead to advanced designs in future meta-analytic research.

Brain↗
PubMed1998

Effects of timolol and betaxolol on choroidal blood flow in the rabbit.

This study evaluated the effects of the topical beta1-adrenergic antagonist betaxolol and the non-selective beta-adrenergic antagonist timolol on the choroidal pressure-flow relationship. Pentobarbital-anesthetized rabbits were instrumented with hydraulic occluders on the aorta and inferior vena cava to control MAP, an ear artery cannula to measure mean arterial pressure (MAP), and two vitreous cannulas to control and measure intraocular pressure (IOP). Choroidal blood flow was measured by laser Doppler flowmetry with the fiber-optic probe tip positioned over the posterior pole. Choroidal pressure-flow curves were obtained before and 30 min after topical application of 0.1 ml of betaxolol (Betoptic, 0.5%, n=10), timolol (Timoptic, 0.5%, n=10) or saline (n=8) by varying the MAP without controlling the IOP and by raising IOP while holding the MAP constant at 70 mmHg. The IOP was significantly reduced by betaxolol and timolol but not by saline. MAP was also slightly, but significantly, reduced after betaxolol but not after timolol or saline. However, the systemic hypotensive response to isoproterenol (8 microgram/kg, i.v.) was blunted after betaxolol and timolol indicating appreciable systemic absorption of both drugs. Timolol, but not betaxolol or saline, caused a significant, small increase in baseline choroidal vascular resistance. Timolol also attenuated the IOP response to MAP; however, none of the treatments had a significant effect on the choroidal pressure-flow relationship. We conclude that both drugs reach the systemic circulation after topical application, but neither betaxolol nor timolol alter the choroidal response to acute changes in perfusion pressure.

Adrenergic beta-Antagonists↗
PubMed2006

Diagnostic imaging of myomas.

As treatment options become less invasive and more sophisticated it is imperative that benign myomas be distinguished from potential malignant conditions without falter. The radiologic-pathologic correlations have been integral to our ability to characterize and to localize uterine leiomyomas with accuracy. TVUS remains the standard assessment tool. Its usefulness may be enhanced by SHG or transabdominal ultrasound in certain circumstances; however, it falls short in its ability to map multiple myomas or those in large volume uteri. MRI has become ultrasound's complement and far exceeds ultrasound's technical limitations in precise fibroid mapping and characterization.

Clinical Trials as Topic↗
PubMed1988

High-performance liquid chromatography in protein sequence determinations.

The use of reversed-phase high-performance liquid chromatography (RP-HPLC) for the determination of protein sequences is reported. Topics considered include the peptide separation of endoprotease digestion mixtures, the application of HPLC peptide mapping as an efficient system to check the accuracy of an assumed protein sequence, obtained indirectly by DNA sequencing and the use of HPLC for amino acid analysis in the Edman sequence strategy. The use of RP-HPLC for an unconventional sequence strategy is demonstrated; HPLC exopeptidase mapping appears to be particularly useful as a future technique for small terminal sequence analysis. Finally, the coupling of HPLC with fast atom bombardment mass spectrometry is discussed.

Acetates↗
PubMed1993

Toward the construction of a molecular map of cassava (Manihot esculenta Crantz): comparison of restriction enzymes and probe sources in detecting RFLPs.

The construction of a detailed genetic map of cassava (Manihot esculenta Crantz), classified as a tetraploid species, depends on the ability of cloned sequences to detect polymorphisms. As a first step in developing this map, 200 cloned nuclear sequences generated with different restriction enzymes were hybridized to total digested DNA from eleven cultivated lines and one wild Manihot species, M. aesculifolia. Polymorphism was detected less frequently with both BamHI and EcoRI genomic probes than with PstI, HindIII and XbaI genomic probes. DNA digested with HpaII, DraI and TaqI displayed less polymorphism, whereas DNA digested with EcoRI and EcoRV displayed more polymorphism like that found in lettuce, rice and tomato (Landry et al., 1987; McCouch et al., 1988; Miller and Tanksley, 1990). Four-cutter restriction enzymes displayed less frequency of polymorphism when compared with six-cutter restriction enzymes. Polymorphism displayed by DraI was extremely low, indicating that regions rich in adenine and thymine may not be hot spots for mutation in cassava. Polymorphism detected between cultivated genotypes and M. aesculifolia was dramatically higher than that found among cultivated genotypes.

DNA Probes↗
PubMedDate not supplied

Determining the permeability of fractured rocks based on joint mapping.

A typical fractured rock mass is intersected by several sets of discontinuities, which provide the main flowpath for ground water. Due to the limitations of data obtained by conventional field measurements, it is often difficult to estimate the anisotropic permeability tensor associated with the joints existing in the rock mass. For that reason, determining permeability tensors for fractured rocks is an important topic in rock mass hydraulics. Based on field surveys, joint parameters can be analyzed by using probabilistic and statistical tools, and three-dimensional mapping of the jointed rock mass. Through analysis of a single joint's hydraulic characteristics, the principal value of the permeability tensor for the jointed rock mass can be determined by using Monte Carlo methods and the searching percolation trace method, which is developed in this paper. The study reports on practical examples demonstrating that results from the methods discussed in this paper are in agreement with those from field hydrogeological surveys and measurements.

Data Collection↗
PubMed2006

Effects of Yahom on the regional cerebral blood flow in rat using fluorescence videomicroscopy.

This study was conducted to investigate effects of Yahom on the regional cerebral blood flow (rCBF) in rats using fluorescence videomicroscopy. Male Wistar Furth rats weighing 200-250 g were used, and divided into three groups: experimental I, II and control groups. The experimental I and II groups received single oral administration of Yahom 2 and 4 g/kg.bw, and topical application of Yahom on the pial cerebral cortex, respectively, while the control group received oral administration of 1 ml of 5% Tween. The rCBF was monitored using laser Doppler flowmetry at different periods (5-120 minutes) after the administration of Yahom or Tween. The mean arterial pressure (MAP) was measured through a femoral artery. The cerebral microcirculation was observed and recorded under an intravital fluorescence videomicroscopic system. The arteriolar diameter was measured based on the recorded videomicroscopic images. The MAP and rCBF increased after the oral administration of Yahom, while they did not alter in the control group. The maximum responses of MAP and rCBF were approximately 16% and 33% at 45 min and 30 min after the administration of Yahom 4 g/kg.bw, respectively. The topical application of Yahom induced vasodilation in the pial microvessels. In conclusion, single oral administration of Yahom may increase the regional cerebral blood flow under the effect of cerebral microvascular vasodilation.

Animals↗