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Biomedical subjects

A F Wilson

Publications and source records attributed to A F Wilson.

At least 19 recordsLinked to original sources
PubMed2006

Quantitative genetic analysis of blood pressure reactivity to orthostatic tilt using principal components analysis.

Blood pressure (BP) reactivity to orthostatic tilt may be predictive of cardiovascular disease. However, the genetic and environmental influences on BP reactivity to tilt have not been well examined. Identifying different influences on BP at rest and BP during tilt is complicated by the intercorrelation among multiple measurements. In this study, we use principal components analysis (PCA) to reduce multivariate BP data into components that are orthogonal. The objective of this study is to characterize and examine the genetic architecture of BP at rest and during head-up tilt (HUT). Specifically, we estimate the heritability of individual BP measures and three principal components (PC) derived from multiple BP measurements during HUT. Additionally, we estimate covariate effects on these traits. The study sample consisted of 444 individuals, distributed across four large families. HUT consisted of 70 degrees head-up table tilting while strapped to a tilt table. BP reactivity (deltaBP) was defined as BP during HUT minus BP while supine. Three PC extracted from the PCA were interpreted as 'general BP' (PC1), 'pulse pressure' (PC2) and 'BP reactivity' (PC3). Variance components methods were used to estimate the heritabilities of resting BP, HUT BP, deltaBP, as well as the three BP PC. Significant (P<0.05) heritabilities were found for all BP measurements, except for systolic deltaBP at 1 and 3 min, and diastolic deltaBP at 2 min. Significant genetic effects were also found for the three PC. Each of these orthogonal components is significantly influenced by somewhat different sets of covariates.

Adolescent↗
PubMed2003

A study of linkage and association of body mass index in the Old Order Amish.

Obesity is thought to have a genetic component with the estimates of heritability ranging from 0.25-0.40. As part of an ongoing study of obesity in the Old Order Amish, seven two- and three-generation families (157 individuals) were assessed for 21 traits related to obesity, including body mass index (BMI) and BMI-percentile (a standardized distribution of BMI adjusted for age and sex). Genotyping was performed using a panel of 384 short-tandem repeat markers. In this sample, the estimates of heritability ranged from 0.16-0.31 for BMI and from 0.40-0.52 for BMI-percentile. Model-independent linkage analysis identified candidate regions on chromosomes 1, 5, 7, 8, and 11. Given that several markers on 7q were significant for both BMI and BMI-percentile (P < or = 0.001) and that the structural locus for leptin was located on 7q, this region was considered to be the primary candidate region. Subsequent typing of additional flanking markers on 7q corroborated the original findings. Tests of intrafamilial association for alleles at markers in this candidate region were significant at similar levels. Although there is some evidence for linkage and association in the region containing leptin, there appears to be stronger evidence for linkage (P < or = 0.001) and association (P < or = 0.00001) with BMI in a region 10-15 cM further downstream of leptin, flanked by markers D7S1804 and D7S3070 with peak values from D7S495-D7S1798. Evidence from linkage and association studies suggests that this region (D7S1804-D7S3070) may be responsible, at least in part, for variation in BMI and BMI-percentile in the Old Order Amish.

Alleles↗
PubMed2001

Effects of misspecification of allele frequencies on the power of Haseman-Elston sib-pair linkage method for quantitative traits.

It is well known that the Haseman-Elston (H-E) sib-pair linkage method does not assume that the genetic model underlying the trait phenotype is known without error, although this assumption is made for marker loci. However, misspecification of allele frequencies at the marker locus decreases power when some or all parental genotypes are unknown. In this study, the power of the H-E sib-pair method was compared for different types of traits when some or all parental data were missing and allele frequencies at the marker loci were misspecified. Data were generated for a quantitative trait and marker loci in nuclear families using G.A.S.P. (V3.3). Three types of traits were simulated with two equifrequent alleles with a random environmental effect (10%, 30%, and 50%). The simulated data were analyzed using (i) one of the parent's marker data, and (ii) no parental marker data, with both correct and incorrect marker allele frequencies. This test is found to be robust in most of the situations considered except for a slight decrease in power when sample size is small and when the marker locus is not very polymorphic.

Chromosome Mapping↗
PubMed2001

Comparison of variance components, ANOVA and regression of offspring on midparent (ROMP) methods for SNP markers.

An extension of the traditional regression of offspring on midparent (ROMP) method was used to estimate the heritability of the trait, test for marker association, and estimate the heritability attributable to a marker locus. The fifty replicates of the Genetic Analysis Workshop (GAW) 12 simulated general population data were used to compare the ROMP method with the variance components method as implemented in SOLAR as a test for marker association, and to a standard analysis of variance (ANOVA) method. Large sample statistical properties of the ROMP and ANOVA methods were compared using 2,000 replicates resampled from the families of the original 50 replicates. Overall, the power to detect a completely associated single nucleotide polymorphism (SNP) marker was high, and the type I error rates were similar to nominal significance levels for all three methods. The standard deviations of the estimates of the heritability of the trait were large for both SOLAR and ROMP, but the estimates were, on average, close to those of the generating model for both methods. However, on average, SOLAR overestimated the heritability attributable to the associated SNP marker (by 256%) while ROMP underestimated it (by 26%).

Analysis of Variance↗
PubMed2001

A single-breath technique with variable flow rate to characterize nitric oxide exchange dynamics in the lungs.

Current techniques to estimate nitric oxide (NO) production and elimination in the lungs are inherently nonspecific or are cumbersome to perform (multiple-breathing maneuvers). We present a new technique capable of estimating key flow-independent parameters characteristic of NO exchange in the lungs: 1) the steady-state alveolar concentration (C(alv,ss)), 2) the maximum flux of NO from the airways (J(NO,max)), and 3) the diffusing capacity of NO in the airways (D(NO,air)). Importantly, the parameters were estimated from a single experimental single-exhalation maneuver that consisted of a preexpiratory breath hold, followed by an exhalation in which the flow rate progressively decreased. The mean values for J(NO,max), D(NO,air), and C(alv,ss) do not depend on breath-hold time and range from 280-600 pl/s, 3.7-7.1 pl. s(-1). parts per billion (ppb)(-1), and 0.73-2.2 ppb, respectively, in two healthy human subjects. A priori estimates of the parameter confidence intervals demonstrate that a breath hold no longer than 20 s may be adequate and that J(NO,max) can be estimated with the smallest uncertainty and D(NO,air) with the largest, which is consistent with theoretical predictions. We conclude that our new technique can be used to characterize flow-independent NO exchange parameters from a single experimental single-exhalation breathing maneuver.

Adult↗
PubMed2001

Flow-independent nitric oxide exchange parameters in healthy adults.

Currently accepted techniques utilize the plateau concentration of nitric oxide (NO) at a constant exhalation flow rate to characterize NO exchange, which cannot sufficiently distinguish airway and alveolar sources. Using nonlinear least squares regression and a two-compartment model, we recently described a new technique (Tsoukias et al. J Appl Physiol 91: 477-487, 2001), which utilizes a preexpiratory breath hold followed by a decreasing flow rate maneuver, to estimate three flow-independent NO parameters: maximum flux of NO from the airways (J(NO,max), pl/s), diffusing capacity of NO in the airways (D(NO,air), pl x s(-1) x ppb(-1)), and steady-state alveolar concentration (C(alv,ss), ppb). In healthy adults (n = 10), the optimal breath-hold time was 20 s, and the mean (95% intramaneuver, intrasubject, and intrapopulation confidence interval) J(NO,max), D(NO,air), and C(alv,ss) are 640 (26, 20, and 15%) pl/s, 4.2 (168, 87, and 37%) pl x s(-1) x ppb(-1), and 2.5 (81, 59, and 21%) ppb, respectively. J(NO,max) can be estimated with the greatest certainty, and the variability of all the parameters within the population of healthy adults is significant. There is no correlation between the flow-independent NO parameters and forced vital capacity or the ratio of forced expiratory volume in 1 s to forced vital capacity. With the use of these parameters, the two-compartment model can accurately predict experimentally measured plateau NO concentrations at a constant flow rate. We conclude that this new technique is simple to perform and can simultaneously characterize airway and alveolar NO exchange in healthy adults with the use of a single breathing maneuver.

Adult↗
PubMed2000

Equivalence of single- and multilocus markers: power to detect linkage with composite markers derived from biallelic loci.

The reintroduction of biallelic markers, now in the form of single-nucleotide polymorphisms (SNPs), has again raised concerns about the practicality of the use of markers with low heterozygosity for genomic screening for complex traits, even if thousands of such markers are available. Like the early blood-group markers (e.g., Rh and MNS), tightly linked biallelic SNPs can be combined into composite markers with heterozygosity similar to that of short-tandem-repeat polymorphisms. The assumptions that underlie the equivalence between single-locus multiallelic and composite markers are presented. We used computer simulation to determine the power of the Haseman-Elston test for linkage with composite markers when not all of these assumptions hold. The Genometric Analysis Simulation Program was used to simulate continuous and discrete traits, one single-locus four-allele marker, and six biallelic markers. We studied composite markers created from pairs, trios, and quartets of biallelic markers in nuclear families and in independent sib pairs. The power to detect linkage with a two-point approach for composite markers and with a multipoint approach that incorporated all six biallelic markers was compared with that for a single-locus, four-allele reference marker. Although the power to detect linkage with a single biallelic marker was considerably less than that of the reference marker, the power to detect linkage with two- and three-locus composite markers was quite similar to that of the reference marker. The power to detect linkage with four-locus composite markers was similar to that of a multipoint approach.

Alleles↗
PubMed2000

Model-free sib-pair linkage analysis: combining full-sib and half-sib pairs.

When sampling full-sibs for linkage studies, half-sibs are often available. Not only are half-sibs convenient to sample, but they can sometimes offer greater power than full-sibs. We propose a method to combine the information from full-sibs and half-sibs into a single test for linkage. This method is based on the Haseman and Elston [1972] method of regressing the squared trait-difference for a pair of sibs (either full- or half-sibs) on the estimated proportion of alleles shared identical by descent. To approximate the distribution of the test statistic, we propose a correction factor that considers the correlation among sibs, and demonstrate by simulations that this approximation works well in many situations, although there are some conditions for which the statistic can have an inflated Type-I error rate. The main appeal of our proposed method is the speed at which it can be computed, offering a rapid way to perform genome-wide linkage screens.

Alleles↗
PubMed2000

Relationship between amount of lung resected and outcome after lung volume reduction surgery.

BACKGROUND: Lung volume reduction surgery (LVRS) is being actively investigated for palliative treatment of severe emphysema. Considerable focus is directed toward patient selection and outcomes of LVRS. However, there is little information available regarding surgical methods to guide optimal extent of resection. We hypothesized that acute improvement and long-term survival after bilateral staple LVRS would be related to the extent of tissue resected. METHODS: The relationship between acute improvement in forced expiratory volume in 1 second and forced vital capacity was examined as a function of the total grams of lung tissue resected in 237 patients who underwent bilateral staple LVRS by a single group of surgeons. Overall survival was assessed based on extent of resection by quartiles of tissue weight resected using Kaplan-Meier survival methods. RESULTS: Improvement in forced expiratory volume in 1 second and forced vital capacity correlated with extent of tissue resected (p < 0.01), although there was considerable variability to individual response (r = 0.3). In contrast, there was no apparent relationship between the amount of tissue resected and overall postoperative survival (p = 0.7). CONCLUSIONS: There is a correlation between the amount of tissue resected and improvement in forced expiratory volume in 1 second and forced vital capacity after bilateral staple LVRS, with generally greater postoperative improvement after larger volume resections. However, there does not appear to be greater long-term survival with larger volume resections despite greater improvement in spirometry. This study suggests that factors other than improvement in spirometric variables may govern optimal LVRS resection volumes and long-term outcome. Future studies will clearly be needed in this important area of LVRS emphysema research.

Adult↗
PubMed2000

Effect of alveolar volume and sequential filling on the diffusing capacity of the lungs: I. theory.

The diffusing capacity, DL, is a critical physiological parameter of the lung used to assess gas exchange clinically. Most models developed to analyze experimental data from a single breath maneuver have assumed a well-mixed or uniform alveolar region, including the clinically accepted Jones-Meade method. In addition, all previous models have assumed a constant DL, which is independent of alveolar volume, VA. In contrast, experimental data provide evidence for a non-uniform alveolar region coupled with sequential filling of the lung. In addition, although the DL for carbon monoxide is a weak function of VA, the DL of nitric oxide depends strongly on VA. We have developed a new mathematical model of the single breath maneuver that considers both a variable degree of sequential filling and a variable DL. Our model predicts that the Jones-Meade method overestimates DL when the exhaled gas sample is collected late in the exhalation, but underestimates DL if the exhaled gas sample is collected early in the exhalation phase due to the effect of sequential filling. Utilizing a prolonged constant exhalation method, or a three-equation method, will also produce erroneous predictions of DL. We conclude that current methods may introduce significant error in the estimation of DL by ignoring the sequential filling of the lung, and the dependence of DL on VA.

Humans↗
PubMed2000

Effect of alveolar volume and sequential filling on the diffusing capacity of the lungs: II. Experiment.

The diffusing capacity of the lung, DL, is a critical physiological parameter, yet the currently accepted clinical model (Jones-Meade) assumes a well-mixed alveolar region, and a constant DL independent of alveolar volume, VA, despite experimental evidence to the contrary. We have formulated a new mathematical model [Tsoukias, N.M, Wilson, A.F., George, S.C., 2000. Respir. Physiol. 120, 231-249] that considers variable alveolar mixing through a single parameter, k (0<k<1), and a DL that is a positive function of VA (DL=a+bVA or DL=alphaVA(beta)). The goal of this study is to determine the suitability of this model to determine the unknown parameters a, b, alpha, beta, and k from experimental data in normal subjects. The model predicts that the normal lung fills, in part, sequentially (k=0.51+/-0.35). The following average values in all seven subjects were obtained: DLNO=48.VA(2/3) ml/min/mmHg and DLCO=20+0.7.VA ml/min/mmHg (STPD) where VA is expressed in L (STPD). We conclude that the mathematical model is suitable for identifying the unknown parameters and thus can be used to characterize the degree of alveolar mixing (or sequential filling) as well as the volume dependence of DL.

Adult↗
PubMed2000

Leptin and IGF-I levels in unconditioned male volunteers after short-term exercise.

We have previously shown that serum gonadotropins, particularly LH, decline after acute exercise in male volunteers. The mechanism for this decline is unknown. Plasma leptin and IGF-I concentrations were measured in seven male volunteers after acute exercise to exhaustion using the Bruce protocol. Leptin concentrations declined following exercise reaching nadir values 30-120 min after exercise. As anticipated, plasma IGF-I concentrations showed a transient rise immediately after exercise falling thereafter to nadir levels 60-90 min after exercise before returning towards baseline levels. In view of the previously described decline in gonadotropin release after acute exercise, the decline in plasma leptin levels, perhaps related to the rise in IGF-I, may play a role in exercise-induced inhibition of gonadotropin release presumably by inhibition of GnRH secretion.

Adult↗
PubMed2000

Ketosis with enhanced GABAergic tone promotes physiological changes in transcendental meditation.

Transcendental meditation (TM) is a stylized form of physical and mental relaxation which is associated with changes in the secretion and release of several pituitary hormones. The hormonal changes induced by TM mimic the effects of the inhibitory neurotransmitter gamma aminobutyric acid (GABA). It is hypothesized that TM produces changes in pituitary hormone secretion by enhancing hypothalamic GABAergic tone as a result of TM associated ketosis. Ketosis enhances the entry of glutamate, the amino acid substrate of GABA into synaptosomes, making more glutamate available for conversion to GABA through the glutamate decarboxylase pathway.

Brain↗
PubMed1999

Regional inference with averaged P values increases the power to detect linkage.

Controversy exists with respect to the choice of an appropriate critical value when testing for linkage in a genomic screen. A number of critical values have been proposed for single-locus and multi-locus linkage analyses. In this study, criteria based on multiple single-locus analyses (i.e., regional test criteria) are evaluated using simulation methods for three different map densities. Tests based on single loci, multiple consecutive single loci, and moving averages of consecutive single loci are considered. Appropriate critical values are determined based on results from simulations under the null hypothesis of no linkage. The power of each "regional test " was compared to the power of a single-locus test. Results suggest that the best power was found when averaging P values over an interval size of 9-15 cM, and that testing the average of P values from two consecutive loci is superior to testing each single locus separately. The increase in power ranged from 7- 29% over the simulations considered.

Bias↗
PubMed1999

Environmental covariates: effects on the power of sib-pair linkage methods.

The effect of inclusion of environmental risk factors on the power of sib-pair linkage methods was tested for a qualitative trait. It was found that inclusion of an environmental variable did not increase the power of the Haseman-Elston (H-E) sib-pair nonparametric linkage analysis test. However, a significant increase in power was observed for both the H-E and affected-sib-pair tests, even in small samples, when persons unexposed to the environmental risk factor were coded as unknown.

Environment↗
PubMed1999

Possible linkage of alcoholism, monoamine oxidase activity and P300 amplitude to markers on chromosome 12q24.

Multipoint linkage analysis was used to screen for evidence of linkage between alcoholism and five alcoholism-related quantitative traits. The results suggest that a susceptibility locus that influences monoamine oxidase activity and P300 amplitude at the Pz lead, and increases the risk of alcohol dependence may be linked to markers in the 12q24 region. Furthermore, the susceptibility for alcoholism may be associated with allele 3 (allele size 144) of D12S392.

Alcoholism↗
PubMed1999

Survival after unilateral versus bilateral lung volume reduction surgery for emphysema.

OBJECTIVE: Bilateral staple lung volume reduction surgery (LVRS) immediately improves pulmonary function and dyspnea symptoms in patients with advanced heterogeneous emphysema to a greater degree than do unilateral procedures. However, the long-term outcome after these surgical procedures needs to be critically evaluated. We compare 2-year survival of patients who underwent unilateral versus bilateral video-assisted LVRS in a large cohort treated by a single surgical group. METHODS: The cases of all 260 patients who underwent video-assisted thoracoscopic stapled LVRS from April 1994 to March 1996 were analyzed to compare results after unilateral versus bilateral procedures. Overall survival was calculated by Kaplan-Meier methods; Cox proportional hazard methods were used to adjust for patient heterogeneity and baseline differences between groups. RESULTS: Overall survival at 2 years was 86.4% (95% CI 80. 9%-91.8%) after bilateral LVRS versus 72.6% (95% CI 64.2%-81.2%) after unilateral LVRS (P =.001 for overall survival comparison). Improved survival after bilateral LVRS was seen among high- and low-risk subgroups as well. Average follow-up time was 28.5 months (range, 6 days to 46.6 months) for the bilateral LVRS group and 29.3 months (range, 6 days to 45.0 months) for the unilateral LVRS patients. CONCLUSIONS: Comparison of unilateral versus bilateral thoracoscopic LVRS procedures for the treatment of emphysema reveals that bilateral LVRS by video-assisted thoracoscopy resulted in better overall survival at 2-year follow-up than did unilateral LVRS. This survival study, together with other studies demonstrating improved lung function after bilateral LVRS, suggests that bilateral surgery appears to be the procedure of choice for patients undergoing LVRS for most eligible patients with severe heterogeneous emphysema.

Age Factors↗