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PubMed2004

Identifying adaptive genetic divergence among populations from genome scans.

The identification of signatures of natural selection in genomic surveys has become an area of intense research, stimulated by the increasing ease with which genetic markers can be typed. Loci identified as subject to selection may be functionally important, and hence (weak) candidates for involvement in disease causation. They can also be useful in determining the adaptive differentiation of populations, and exploring hypotheses about speciation. Adaptive differentiation has traditionally been identified from differences in allele frequencies among different populations, summarised by an estimate of FST. Low outliers relative to an appropriate neutral population-genetics model indicate loci subject to balancing selection, whereas high outliers suggest adaptive (directional) selection. However, the problem of identifying statistically significant departures from neutrality is complicated by confounding effects on the distribution of FST estimates, and current methods have not yet been tested in large-scale simulation experiments. Here, we simulate data from a structured population at many unlinked, diallelic loci that are predominantly neutral but with some loci subject to adaptive or balancing selection. We develop a hierarchical-Bayesian method, implemented via Markov chain Monte Carlo (MCMC), and assess its performance in distinguishing the loci simulated under selection from the neutral loci. We also compare this performance with that of a frequentist method, based on moment-based estimates of FST. We find that both methods can identify loci subject to adaptive selection when the selection coefficient is at least five times the migration rate. Neither method could reliably distinguish loci under balancing selection in our simulations, even when the selection coefficient is twenty times the migration rate.

Adaptation, Biological↗

PubMed2001

Complex trait analysis of the mouse striatum: independent QTLs modulate volume and neuron number.

BACKGROUND: The striatum plays a pivotal role in modulating motor activity and higher cognitive function. We analyzed variation in striatal volume and neuron number in mice and initiated a complex trait analysis to discover polymorphic genes that modulate the structure of the basal ganglia. RESULTS: Brain weight, brain and striatal volume, neuron-packing density and number were estimated bilaterally using unbiased stereological procedures in five inbred strains (A/J, C57BL/6J, DBA/2J, BALB/cJ, and BXD5) and an F2 intercross between A/J and BXD5. Striatal volume ranged from 20 to 37 mm3. Neuron-packing density ranged from approximately 50,000 to 100,000 neurons/mm3, and the striatal neuron population ranged from 1.4 to 2.5 million. Inbred animals with larger brains had larger striata but lower neuron-packing density resulting in a narrow range of average neuron populations. In contrast, there was a strong positive correlation between volume and neuron number among intercross progeny. We mapped two quantitative trait loci (QTLs) with selective effects on striatal architecture. Bsc10a maps to the central region of Chr 10 (LRS of 17.5 near D10Mit186) and has intense effects on striatal volume and moderate effects on brain volume. Stnn19a maps to distal Chr 19 (LRS of 15 at D19Mit123) and is associated with differences of up to 400,000 neurons among animals. CONCLUSION: We have discovered remarkable numerical and volumetric variation in the mouse striatum, and we have been able to map two QTLs that modulate independent anatomic parameters.

Animals↗

PubMed2000

Neural coding: higher-order temporal patterns in the neurostatistics of cell assemblies.

Recent advances in the technology of multiunit recordings make it possible to test Hebb's hypothesis that neurons do not function in isolation but are organized in assemblies. This has created the need for statistical approaches to detecting the presence of spatiotemporal patterns of more than two neurons in neuron spike train data. We mention three possible measures for the presence of higher-order patterns of neural activation--coefficients of log-linear models, connected cumulants, and redundancies--and present arguments in favor of the coefficients of log-linear models. We present test statistics for detecting the presence of higher-order interactions in spike train data by parameterizing these interactions in terms of coefficients of log-linear models. We also present a Bayesian approach for inferring the existence or absence of interactions and estimating their strength. The two methods, the frequentist and the Bayesian one, are shown to be consistent in the sense that interactions that are detected by either method also tend to be detected by the other. A heuristic for the analysis of temporal patterns is also proposed. Finally, a Bayesian test is presented that establishes stochastic differences between recorded segments of data. The methods are applied to experimental data and synthetic data drawn from our statistical models. Our experimental data are drawn from multiunit recordings in the prefrontal cortex of behaving monkeys, the somatosensory cortex of anesthetized rats, and multiunit recordings in the visual cortex of behaving monkeys.

Action Potentials↗

PubMed2002

Reason for discrepancies in identifying myocardial viability by thallium-201 redistribution, magnetic resonance imaging, and dobutamine echocardiography.

Dobutamine echocardiography (DE), magnetic resonance imaging (MRI), and thallium redistribution (TS) are used to assess cardiac viability. However, these modalities sometimes yield contradictory results. Our aim was to establish the degrees of agreement among DE, MRI, and TS in identifying myocardial viability and to analyze the minimum critical mass of live (viable) cells required for each test to identify viability. A prospective study was done in which DE, MRI, and TS were consecutively performed in 10 ischemic patients scheduled for heart transplantation. The explanted heart was analyzed to quantify the amount of live cells per segment. The pathologic data were compared with the test results to analyze the minimum mass of viable cells required by each technique to identify viability. Mean age was 58 +/- 8 years (8 men). The mean ejection fraction was 0.27 +/- 0.04. Seven patients had severe cardiac failure (New York Heart Association functional class IV) and 6 patients had refractory angina. A total of 150 cardiac segments were analyzed. Among the 150 segments, 107 (71.3%) showed some degree of myocardial necrosis. Mean total area, mean fatty area, and mean necrotic area per segment were 2.53 +/- 0.7, 0.13 +/- 0.2, and 0.55+/-0.5 cm(2), respectively. As expected, a higher amount of necrotic tissue was found in nonviable segments. From the 150 segments, DE identified 90 as viable and 60 as nonviable. These data were similar to that of MRI (98 viable and 52 nonviable). A higher proportion of viable segments was found by TS (117 viable vs 33 nonviable). The concordance between DE and TS was only moderate (kappa 0.49). The agreement between MRI and TS also showed moderate concordance (kappa 0.56). The highest agreement was found between DE and MRI (kappa 0.73). Thus, discrepancies in assessing viability by DE, MRI, and TS may be due to differences in the minimum critical mass of live myocytes required by each technique to diagnose viability. Thallium requires a lesser amount of live tissue than DE or MRI to detect viability; also, its maximum diagnostic efficiency is obtained with lesser amounts of live tissue on each segment. These considerations should be taken into account when these diagnostic tests are used for the detection of viability before revascularization procedures.

Aged↗

PubMed2003

The accuracy of the amblyopia treatment study visual acuity testing protocol.

PURPOSE: To study the accuracy of the newly proposed Amblyopia Treatment Study (ATS) visual acuity testing protocol for 3- to 6-year-old children. Because no "gold standard" is available for acuity testing in pediatric patients, accuracy was evaluated using computer simulations based on a psychometric model. METHODS: Monte Carlo simulations of ATS acuity data were generated using a psychometric model that accounts for true acuity, noise in the visual system, and the rate of inadvertent misses. We varied true acuity from 20/15 to 20/400 (-0.1 to 1.3 logMAR). Visual system noise was represented by the slope beta of the psychometric function and ranged from 1 (noisy) to 8 (not noisy). The rate of inadvertent misses ranged from 0% to 10%. Accuracy of the ATS protocol was evaluated in terms of precision, bias, and stimulus range limitations. The same model was fitted to experimental ATS acuity data, thus allowing us to study the distributions of acuity, visual system noise, and level of attentiveness in 126 children ages 3 to <7 years. RESULTS: For conditions with little noise in the visual system (beta > 2), precision was well within 0.1 logMAR (corresponding to one line on a logMAR letter chart), except for acuities worse than 1.2 logMAR, and decreased to 0.15 to 0.2 logMAR for beta = 1. Bias was negligible, except in noisy conditions, where the ATS protocol tended to overestimate acuity by one line at the poor end of the true acuity range and underestimate acuity at the good end of the true acuity range. Effects of the rate of inadvertent misses were small. Fits to the real data showed a wide range of slope parameters, but only 11% had beta < or = 2. The rate of inadvertent misses was < or = 2% in 89% of cases. CONCLUSION: The simulations suggest that the ATS protocol offers an accurate method for assessing visual acuity in children in the range of 3 to 6 years of age with both precision and bias within 0.1 logMAR for typical values of the psychometric parameters.

Amblyopia↗

PubMed2001

Relative impact of patient and clinic factors on adherence to primary care preventive service guidelines: an exploratory study.

BACKGROUND: Preventive care service use is commonly compared across health plans, clinics, or individual providers, yet little is known about the influence of the clinic versus patient factors on utilization of these services. OBJECTIVES: To measure the relative influence of the facility (clinic) versus patient factors (demographic, behavioral and functional characteristics) on patients' utilization of mammography, Pap smears, cholesterol screening, and retinal exams for those with diabetes. RESEARCH DESIGN: Retrospective analysis, using administrative and patient survey data. SUBJECTS: Enrollees in 2 University-based clinics and a county hospital-based clinic serving a predominantly low-income population with limited access to health care. Eligibility for cervical cancer screening, screening mammography, cholesterol screening, or annual retinal exam (diabetes) was defined by age, sex, and diagnosis. MEASURES: Multivariate models, one using readily available administrative data, and another using detailed health status and behavior data gathered from a clinics-wide survey. RESULTS: Unadjusted screening rates for three of four procedures were significantly and substantially lower at the county hospital based clinic than the two University-based clinics. After adjusting for patient characteristics, utilization of three screening services at the county hospital remained significantly below the University-based clinics (Odds Ratios [95% CI]: mammogram 0.15 [0.06-0.35]; Pap smear 0.32 [0.21-0.50]; cholesterol 0.19 [0.09-0.38]; diabetes retinal exam10.68 [0.93-3.01]). The models with detailed survey data performed only marginally better than the models using only administrative data. CONCLUSIONS: Patient characteristics were much less important than the clinic for predicting whether patients received primary care preventive services. Our results suggest that case mix adjustment is unlikely to explain away discrepancies in performance between clinics or provider groups.

Adult↗

PubMed2005

The geographic spread of the CCR5 Delta32 HIV-resistance allele.

The Delta32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Delta32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Delta32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Delta32 allele, we implemented a spatially explicit model of the spread of Delta32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Delta32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Delta32 allele is consistent with previous reports of a strong selective advantage (>10%) for Delta32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Delta32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Delta32 allele and establish a general methodology for studying the geographic distribution of selected alleles.

Alleles↗

PubMed1992

Fractionation sensitivity and latency of late radiation injury to the mouse urinary bladder.

Transurethral bladder filling is a functional, non-invasive, in vivo assay of early and late radiation injury to the mouse bladder. Fractionated irradiations using single doses or 2, 3, 5, or 10 dose fractions in an overall time of 4 or 4.5 days, with a range of total doses, were given to the bladder of 12-14 week-old C3D2F1/Bom mice. In 372 mice, bladder volume at an intravesical pressure of 20 mmHg was measured before irradiation and at regular intervals thereafter. The endpoint for late bladder injury was a volume of less than 50% of the median pretreatment volume in all animals, occurring more than 30 days after irradiation. This endpoint was reached after a latent period ranging between 35 and 401 days. Fractionation and latency parameters were estimated using a mixture model. There was a highly statistically significant dose-dependency of the latent period (p < 10(-8)). The alpha/beta ratio was estimated at 5.8 Gy [95% confidence limits (3.6; 8.8) Gy] for 250 kVp X-rays. Thus late radiation injury in the mouse urinary bladder is one of the least sensitive late endpoints with respect to change in dose per fraction. Introducing early bladder injury as a variable in the model improved the fit significantly (p = 0.03), but the alpha/beta ratio remained unchanged. Thus the hypothesis that late bladder injury may be, at least in part, consequent upon early injury did not explain the relatively high alpha/beta ratio for this late endpoint.

Animals↗

PubMed2005

Haplotype association analysis of human disease traits using genotype data of unrelated individuals.

Haplotype inference has become an important part of human genetic data analysis due to its functional and statistical advantages over the single-locus approach in linkage disequilibrium mapping. Different statistical methods have been proposed for detecting haplotype - disease associations using unphased multi-locus genotype data, ranging from the early approach by the simple gene-counting method to the recent work using the generalized linear model. However, these methods are either confined to case - control design or unable to yield unbiased point and interval estimates of haplotype effects. Based on the popular logistic regression model, we present a new approach for haplotype association analysis of human disease traits. Using haplotype-based parameterization, our model infers the effects of specific haplotypes (point estimation) and constructs confidence interval for the risks of haplotypes (interval estimation). Based on the estimated parameters, the model calculates haplotype frequency conditional on the trait value for both discrete and continuous traits. Moreover, our model provides an overall significance level for the association between the disease trait and a group or all of the haplotypes. Featured by the direct maximization in haplotype estimation, our method also facilitates a computer simulation approach for correcting the significance level of individual haplotype to adjust for multiple testing. We show, by applying the model to an empirical data set, that our method based on the well-known logistic regression model is a useful tool for haplotype association analysis of human disease traits.

Computer Simulation↗

PubMed1997

Is insulin an independent risk factor for hypertension? The Paris Prospective Study.

BACKGROUND: The link between hyperinsulinaemia and hypertension has been examined in few prospective studies and often diminished after adjustment for obesity, central adiposity and baseline blood pressures. METHODS: The incidence of hypertension was studied as a function of baseline insulin and glucose in 4149 Caucasian, non-hypertensive, non-diabetic middle-aged men from the Paris Prospective Study. Blood pressures were measured over the 3 years of follow-up; hypertension incidence was defined as systolic blood pressure > or = 160 mmHg or diastolic blood pressure > or = 95 mmHg or drug treatment for hypertension. RESULTS: Fasting and 2-hour glucose and insulin were predictive of hypertension, after controlling for the known risk factors: age, excessive alcohol consumption and family history of hypertension (FHH). However, after further controlling for body mass index and central adiposity (the iliac circumference), insulin was no longer predictive in men without an FHH. When weight variation was also taken into account, and further adjustment made for baseline blood pressure and heart rate, fasting insulin, only, was predictive when the subject had a weight increase, independently of FHH. Fasting glucose was predictive of hypertension except in the case of no change or weight decrease and a negative FHH; 2-hour glucose was predictive in the presence of a positive FHH. CONCLUSIONS: Insulin and glucose levels were both risk factors for hypertension, and this risk was enhanced in the case of a positive FHH. However, obesity, especially central obesity, confounded these relationships and might be an intermediary factor in the relationship between insulin and hypertension.

Adult↗

PubMed1999

Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects.

This study is a comprehensive analysis of the latest follow-up of the Colorado uranium miners cohort using the two-stage clonal expansion model with particular emphasis on effects related to age and exposure. The model provides a framework in which the hazard function for lung cancer mortality incorporates detailed information on exposure to radon and radon progeny from hard rock and uranium mining together with information on cigarette smoking. Even though the effect of smoking on lung cancer risk is explicitly modeled, a significant birth cohort effect is found which shows a linear increase in the baseline lung cancer risk with birth year of the miners in the cohort. The analysis based on the two-stage clonal expansion model suggests that exposure to radon affects both the rate of initiation of intermediate cells in the pathway to cancer and the rate of proliferation of intermediate cells. However, in contrast to the promotional effect of radon, which is highly significant, the effect of radon on the rate of initiation is found to be not significant. The model is also used to study the inverse dose-rate effect. This effect is evident for radon exposures typical for mines but is predicted to be attenuated, and for longer exposures even reversed, for the more protracted and lower radon exposures in homes. The model also predicts the drop in risk with time after exposure ceases. For residential exposures, lung cancer risks are compared with the estimates from the BEIR VI report. While the risk estimates are in agreement with those derived from residential studies, they are about two- to fourfold lower than those reported in the BEIR VI report.

Age Factors↗

PubMed1994

Effect of cement film thickness on the fracture resistance of a machinable glass-ceramic.

OBJECTIVES: The aim of this study was to determine the fracture resistance of a machinable glass-ceramic plate cemented to a resin composite block as a function of the cement film thickness for two types of cement. METHODS: Ceramic plates were cemented to resin composite blocks using either zinc phosphate cement or a resin composite cement. For the zinc phosphate cement, the film thickness was 33 +/- 8 microns or 128 +/- 8 microns; for the resin composite cement, the thickness ranged from 26 +/- 11 microns to 297 +/- 48 microns. The elastic modulus was determined for each of the cements. Fracture loads were obtained by using a spherical steel indenter in the center of the glass-ceramic plate. The Weibull distribution was used for the statistical analysis. RESULTS: For glass-ceramic plates cemented with zinc phosphate cement, the fracture resistance was independent of the film thickness. When the resin composite cement was used, a gradual decrease of the fracture strength was observed that became statistically significant at a cement thickness of 300 microns or more. The characteristic fracture strength of glass-ceramic plates cemented with the resin composite cement was about 75% higher than when using the zinc phosphate cement. This difference is attributed to the bonding of the resin cement to the ceramic plate and the supporting structure. SIGNIFICANCE: The findings of this study suggest that the resistance to fracture due to indentation of the glass-ceramic may not be affected by the cement film thickness as much as previously thought.

Acrylic Resins↗

PubMed2001

Stereoacuity thresholds in the presence of a reference surface.

With isolated binocular targets, the best depth discrimination is found in the fixation plane (Blakemore, C., Journal of Physiology 211 (1970) 599). More recent studies have suggested that stereoscopic thresholds are not always a simple function of absolute disparity, but depend on the relative disparities in the stimulus. Here, we explored the effects of relative disparity in more detail, taking particular care to control for the possibility that subjects might change their binocular eye position or exploit monocular information provided by additional reference cues. Subjects judged the depth of a vertical target line presented above a comparison line in a blank window within a fronto-parallel reference surface composed of randomly positioned dots. On individual trials, the reference surface was presented at one of three disparities (-10, 0 and +10 arc min). To control for changes in binocular eye position, exposure duration was 150 ms, and experimental conditions with different disparities of the reference surface and comparison line were randomly interleaved. To control for monocular cues, changes in threshold were determined with respect to a disparity noise condition that was in all ways identical to the reference plane condition, except that the disparities of the dots were randomly assigned between 10 and +10 arc min. Stereo-thresholds were lowered by a factor of about 2 when the surface was at the same depth as the comparison line. Thresholds were also lowered when the comparison disparity was close to the same depth as the reference surface, but were often raised when the comparison disparity had the opposite disparity sign. These results provide unequivocal evidence that the fundamental sensitivity of the disparity detecting system can be influenced by relative disparity cues that are not related to the task.

Confidence Intervals↗

PubMed2004

Covariance functions and random regression models for cow weight in beef cattle.

Data from the first four cycles of the Germplasm Evaluation program at the U.S. Meat Animal Research Center were used to evaluate weights of Angus, Hereford, and F1 cows produced by crosses of 22 sire and 2 dam (Angus and Hereford) breeds. Four weights per year were available for cows from 2 through 8 yr of age (AY) with age in months (AM). Weights (n = 61,798) were analyzed with REML using covariance function-random regression models (CF-RRM), with regression on orthogonal (Legendre) polynomials of AM. Models included fixed regression on AM and effects of cow line, age in years, season of measurement, and their interactions; year of birth; and pregnancy-lactation codes. Random parts of the models fitted RRM coefficients for additive (a) and permanent environmental (c) effects. Estimates of CF were used to estimate covariances among all ages. Temporary environmental effects were modeled to account for heterogeneity of variance by AY. Quadratic fixed regression was sufficient to model population trajectory and was fitted in all analyses. Other models varied order of fit and rank of coefficients for a and c. A parsimonious model included linear and quartic regression coefficients for a and c, respectively. A reduced cubic order sufficed for c. Estimates of all variances increased with age. Estimates for older ages disagreed with estimates using traditional bivariate models. Plots of covariances for c were smooth for intermediate, but erratic for extreme ages. Heritability estimates ranged from 0.38 (36 mo) to 0.78 (94 mo), with fluctuations especially for extreme ages. Estimates of genetic correlations were high for most pairs of ages, with the lowest estimate (0.70) between extreme ages (19 and 103 mo). Results suggest that although cow weights do not fit a repeatability model with constant variances as well as CF-RRM, a repeatability model might be an acceptable approximation for prediction of additive genetic effects.

Age Factors↗

PubMed2005

Rate variation in parasitic plants: correlated and uncorrelated patterns among plastid genes of different function.

BACKGROUND: The analysis of synonymous and nonsynonymous rates of DNA change can help in the choice among competing explanations for rate variation, such as differences in constraint, mutation rate, or the strength of genetic drift. Nonphotosynthetic plants of the Orobanchaceae have increased rates of DNA change. In this study 38 taxa of Orobanchaceae and relatives were used and 3 plastid genes were sequenced for each taxon. RESULTS: Phylogenetic reconstructions of relative rates of sequence evolution for three plastid genes (rbcL, matK and rps2) show significant rate heterogeneity among lineages and among genes. Many of the non-photosynthetic plants have increases in both synonymous and nonsynonymous rates, indicating that both (1) selection is relaxed, and (2) there has been a change in the rate at which mutations are entering the population in these species. However, rate increases are not always immediate upon loss of photosynthesis. Overall there is a poor correlation of synonymous and nonsynonymous rates. There is, however, a strong correlation of synonymous rates across the 3 genes studied and the lineage-speccific pattern for each gene is strikingly similar. This indicates that the causes of synonymous rate variation are affecting the whole plastid genome in a similar way. There is a weaker correlation across genes for nonsynonymous rates. Here the picture is more complex, as could be expected if there are many causes of variation, differing from taxon to taxon and gene to gene. CONCLUSIONS: The distinctive pattern of rate increases in Orobanchaceae has at least two causes. It is clear that there is a relaxation of constraint in many (though not all) non-photosynthetic lineages. However, there is also some force affecting synonymous sites as well. At this point, it is not possible to tell whether it is generation time, speciation rate, mutation rate, DNA repair efficiency or some combination of these factors.

Cell Nucleus↗

PubMed2005

Quantitative inference of dynamic regulatory pathways via microarray data.

BACKGROUND: The cellular signaling pathway (network) is one of the main topics of organismic investigations. The intracellular interactions between genes in a signaling pathway are considered as the foundation of functional genomics. Thus, what genes and how much they influence each other through transcriptional binding or physical interactions are essential problems. Under the synchronous measures of gene expression via a microarray chip, an amount of dynamic information is embedded and remains to be discovered. Using a systematically dynamic modeling approach, we explore the causal relationship among genes in cellular signaling pathways from the system biology approach. RESULTS: In this study, a second-order dynamic model is developed to describe the regulatory mechanism of a target gene from the upstream causality point of view. From the expression profile and dynamic model of a target gene, we can estimate its upstream regulatory function. According to this upstream regulatory function, we would deduce the upstream regulatory genes with their regulatory abilities and activation delays, and then link up a regulatory pathway. Iteratively, these regulatory genes are considered as target genes to trace back their upstream regulatory genes. Then we could construct the regulatory pathway (or network) to the genome wide. In short, we can infer the genetic regulatory pathways from gene-expression profiles quantitatively, which can confirm some doubted paths or seek some unknown paths in a regulatory pathway (network). Finally, the proposed approach is validated by randomly reshuffling the time order of microarray data. CONCLUSION: We focus our algorithm on the inference of regulatory abilities of the identified causal genes, and how much delay before they regulate the downstream genes. With this information, a regulatory pathway would be built up using microarray data. In the present study, two signaling pathways, i.e. circadian regulatory pathway in Arabidopsis thaliana and metabolic shift pathway from fermentation to respiration in yeast Saccharomyces cerevisiae, are reconstructed using microarray data to evaluate the performance of our proposed method. In the circadian regulatory pathway, we identified mainly the interactions between the biological clock and the photoperiodic genes consistent with the known regulatory mechanisms. We also discovered the now less-known regulations between crytochrome and phytochrome. In the metabolic shift pathway, the casual relationship of enzymatic genes could be detected properly.

Algorithms↗

PubMed1996

Choosing optimal values of FEV1 and FEV1/FVC for surveillance for respiratory disorders in occupational populations.

Pulmonary lung-function testing plays an important role in surveillance programs for occupational respiratory disorders. Spirometry is usually utilized by applying preset cut-off values to discriminate between healthy and unhealthy subjects. This article demonstrates the usefulness of decision analysis techniques to arrive at an optimal diagnosis. The diagnostic performance of FEV1 and FEV1/FVC was evaluated by relative operating characteristics curves (ROCs) applied to data of a cohort gathered in 1965. Both parameters showed quite similar ROCs, with a maximal sensitivity of 40% at a specificity of 95% relative to the physician's diagnosis of respiratory disorder. The area under the curves was. 75 for both FEV1 and FEV1/FVC, illustrating that misclassification of 25% of the subjects is likely to occur. Regarding the consequences of a false-positive and a false-negative decision as of equal importance, the 5%-percentile (FEV1 residual less than -1.2 L) would be the optimal cut-off. An FEV1 residual below the lower 5%-percentile was six times more likely to appear in subjects with chronic nonspecific lung disease (CNSLD) than in subjects without. The post-test probability of CNSLD was three to four times the pre-test probability. In occupational or public health practice, however, false-positive results need to be avoided, even at the expense of a higher false-negative rate. In those situations, a more rigid cut-off between normal and abnormal values may be warranted.

Adult↗

PubMed2005

The repertoire of trace amine G-protein-coupled receptors: large expansion in zebrafish.

Trace amines, such as tyramine, beta-phenylethylamine, tryptamine, and octopamine, are present in trace levels in nervous systems and bind a specific family of G-protein-coupled receptors (GPCR), but the function or origin of this system is not well understood. We searched the genomes of several eukaryotic species for receptors similar to the mammalian trace amine (TA) receptor subfamily. We identified 18 new receptors in rodents that are orthologous to the previously known TA-receptors. Remarkably, we found 57 receptors (and 40 pseudogenes) of this type in the zebrafish (Danio rerio), while fugu (Takifugu rubripes) had only eight receptors (and seven pseudogenes). We mapped 47 of the zebrafish TA-receptors on chromosomes using radiation hybrid panels and meiotic mapping. The results, together with the degree of conservation and phylogenetic relationships displayed among the zebrafish receptors suggest that the family arose through several different mechanisms involving tetraploidization, block duplications, and local duplication events. Interestingly, these vertebrate TA-receptors do not show a close evolutionary relationship to the invertebrate TA-binding receptors in fruitfly (Drosophila melanogaster), indicating that the ability to bind TA have evolved at least twice in animal evolution. We collected in total over 100 vertebrate TA-receptor sequences, and our phylogenetic analysis shows that several TA-receptors have evolved rapidly with remarkable species variation and that the common ancestor of vertebrate TA-receptors arose before the split of the ray-finned and lobe-finned fishes. The evolutionary history of the TA-receptors is more complex than for most other GPCR families and here we suggest a mechanism by which they may have arisen.

Amino Acid Sequence↗