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PubMed2005

A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility.

Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.

Black or African American↗
PubMed2000

A likelihood-based extended admixture model of oligogenic inheritance in 'model-based' and 'model-free' analysis.

The admixture test of linkage heterogeneity is the most often and most successfully applied oligogenic-model linkage and/or LD analysis method. Full two-locus model linkage analysis is possible, but can be computationally intensive and difficult to interpret because of the need to specify so many indeterminate parameters. A novel, computationally efficient method is proposed for combining single locus lod scores which can allow for varying degrees of epistatic interaction. This method can be applied to two-point or multipoint (using complex-valued recombination fractions) linkage and/or linkage disequilibrium analysis to jointly test for multiple unlinked disease loci. Unlike the traditional admixture test, this algorithm permits joint analysis of multiple disease loci with different modes of inheritance for each, and can be applied to 'model-free' analysis as well through the use of 'pseudomarkers'. Software is available for computation of the various likelihood ratio tests described, for comparison of a variety of possible hypotheses regarding locus homogeneity, locus heterogeneity, and epistasis.

Algorithms↗
PubMed1999

Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture for drug users in methadone maintenance.

BACKGROUND: Tuberculosis is common in drug users, although compliance with therapy may be difficult in this population. OBJECTIVE: To evaluate an approach to enhancing compliance with tuberculosis chemoprophylaxis in drug users enrolled on methadone maintenance utilizing an isoniazid (INH)-methadone admixture. DESIGN: A prospective cohort study. SETTING: A drug treatment program in New Haven, Connecticut, USA. PATIENTS: Opioid-dependent drug users enrolled in methadone maintenance. INTERVENTION: Liquid isoniazid was mixed into subjects' daily dose of methadone. Vitamin B6 was given to subjects for self-administration. MEASUREMENTS AND MAIN RESULTS: Number of eligible subjects, reasons for not starting therapy, number starting therapy, proportion completing therapy and median duration of INH therapy were calculated. Thirty-nine subjects were eligible for INH chemoprophylaxis: 34 (87%) received INH mixed directly in their methadone and five (13%) had their INH consumption supervised by a nurse. Among these subjects, 72% (28/39) completed therapy. Among the 11 subjects who discontinued INH, discharge from the methadone maintenance program was the most common reason--73% (8/11). Thus, among the 31 subjects who were not discharged from methadone maintenance, 90% (28/31) successfully completed INH prophylaxis. The median duration of therapy was 182 days. CONCLUSIONS: Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture appears to be an effective approach to enhancing compliance with this therapy in methadone-maintained drug users.

Antitubercular Agents↗
PubMed2003

Gene admixture in the Costa Rican population.

The general population of Costa Rica has sometimes been considered to be the product of an amalgamation of groups of diverse origin. To determine the magnitude of accumulated admixture since Spanish colonization, 11 classic genetic markers were analyzed in a total of 2196 individuals originating from five distinct regions of the country. A maximum likelihood approach was used. The proportions of genes of European, Amerindian and African ancestry were found to be 61%, 30% and 9% of the total population, respectively. Variation was observed at a regional level, with an increased European influence in the North (66%) and Central (65%) regions. Meanwhile an increase in Amerindian ancestry was found in the South (38%), and a higher incidence in the contribution of African genes was detected in the coastal regions (13% in the Atlantic and 14% in the North Pacific). A principal component (PC) analysis showed that 76% of the existing variability can be explained by the first two PCs, which is in agreement with the variations observed in the admixture process by geographic area. It has been concluded that the Costa Rican population is truly trihybrid, similar to populations in other Latin American countries; however, it differs from them fundamentally by the proportion of gene flow from ancestral populations.

Blood Group Antigens↗
PubMed1971

The population variance of the proportion of genetic admixture in human intergroup hybrids.

For each individual in a human hybrid population there is a proportion mu(i), whose value is usually unknown, that expresses the fraction of his genes deriving from a specified parental population. The distribution of these individual proportions about the mean proportion mu is not known for any large hybrid population in man. It is of interest to know whether the population variance of individual proportions (mu(i)) can be estimated from the variation between different, independent estimates of the mean proportion (mu). This possibility was tested with data on Negroes of the Oakland, California area, by the use of some of the principles of analysis of variance. Even with a large sample and the useful Duffy blood-group system to indicate admixture, almost no information about the population variance of individual proportions is provided by between-sample variation in estimates of mu. It is concluded that group data on admixture proportions usually do not give useful information about the population variance. It is further concluded that a recent estimate of this variance by Shockley is in error.

Black or African American↗
PubMedDate not supplied

Gene diversity and estimation of genetic admixture among Mexican-Americans of Starr County, Texas.

The Mexican-Americans of Starr County, Texas, classified by sex and birthplace, were studied to determine the extent of genetic variation and contributions from ancestral populations such as Spanish, Amerindian and West African. Using 21 genetic marker systems, genetic distance and diversity analyses indicate that subpopulations of Mexican-Americans in Starr County are similar, and that more than 99% of the total gene diversity (HT) can be attributed to individual variation within the population. Genetic admixture analysis shows the predominant influence comes from the Spanish, a lesser contribution from Amerindians and a slight one from the West Africans. The contribution of the ancestral population to various subpopulations of the Mexican-Americans of Starr County is similar. The Mexican-Americans of Starr County are similar to the Mexican population from northeastern Mexico. The history of admixture is apparently old enough to have brought the entire Mexican-American gene pool to Hardy-Weinberg equilibrium. There is no non-random association of alleles among the genetic marker systems considered in the present study, in spite of the fact that this population is of admixed origin. These results, in aggregate, suggest genetic homogeneity of the Mexican-Americans of Starr County, Texas, and point towards the utility of this population for genetic and epidemiological studies.

Africa↗
PubMed1996

Excess admixture proportion of extended major histocompatability complex haplotypes of Caucasian origin among rheumatoid arthritis associated haplotypes in African Americans and Afro-Caribbeans.

Several extended major histocompatability complex (MHC) haplotypes are associated with susceptibility to autoimmune disease in Caucasian populations. It is known that African Americans and Afro-Caribbeans are ethnic groups descended from west, central and southern black African populations which are admixed with Caucasians. To examine the possible association of some marker of Caucasian MHC genes and susceptibility to rheumatoid arthritis (RA) in African Americans, we studied extended MHC haplotypes (HLA-B, complement and DR) in a sample of 18 African American and Afro-Caribbean probands with RA, their first degree relatives and in 15 non-RA families. We defined 36 disease-associated RA haplotypes among the probands and 96 normal haplotypes in normal individuals. To obtain the most conservative estimate, we excluded recognized Caucasian, DR4-bearing, extended MHC haplotypes from the analysis. Admixture proportions for non-HLA-DR4 extended MHC haplotypes of known Caucasian origin among RA-associated and normal haplotypes were computed (0.40 versus 0.163 respectively). When we compared the difference in proportions between RA and normal haplotypes, the proportion of extended MHC haplotypes of known Caucasian origin was significantly increased among RA-associated haplotypes (Z = 3.16, p (one sided) < 0.001, p (adjusted) < 0.008). Our results suggest that racial admixture with Caucasian MHC genes may augment RA susceptibility and thus may be one mechanism to explain the higher prevalence of RA in African Americans and Afro-Caribbeans than in black African populations.

Arthritis, Rheumatoid↗
PubMed2000

Consistent long-range linkage disequilibrium generated by admixture in a Bantu-Semitic hybrid population.

Both the optimal marker density for genome scans in case-control association studies and the appropriate study design for the testing of candidate genes depend on the genomic pattern of linkage disequilibrium (LD). In this study, we provide the first conclusive demonstration that the diverse demographic histories of human populations have produced dramatic differences in genomewide patterns of LD. Using a panel of 66 markers spanning the X chromosome, we show that, in the Lemba, a Bantu-Semitic hybrid population, markers </= approximately 21 cM apart have a significantly greater tendency to show LD than do unlinked markers. In three populations with less evidence of admixture, however, excess LD disappears >2 cM. Moreover, analysis of Bantu and Ashkenazi populations as putative parental populations of the Lemba shows a significant relationship between allele-frequency differentials and the LD observed in the Lemba, which demonstrates that much of the excess LD is due to admixture. Our results suggest that demographic history has such a profound effect on LD that it will not be possible to predict patterns a priori but that it will be necessary to empirically evaluate the patterns in all populations of interest.

Black People↗
PubMed2001

Markers for mapping by admixture linkage disequilibrium in African American and Hispanic populations.

Population linkage disequilibrium occurs as a consequence of mutation, selection, genetic drift, and population substructure produced by admixture of genetically distinct ethnic populations. African American and Hispanic ethnic groups have a history of significant gene flow among parent groups, which can be of value in affecting genome scans for disease-gene discovery in the case-control and transmission/disequilibrium test designs. Disease-gene discovery using mapping by admixture linkage disequilibrium (MALD) requires a map of polymorphic markers that differentiate between the founding populations, along with differences in disease-gene allele frequencies. We describe markers appropriate for MALD mapping by assessing allele frequencies of 744 short tandem repeats (STRs) in African Americans, Hispanics, European Americans, and Asians, by choosing STR markers that have large differences in composite delta, log-likelihood ratios, and/or I*(2) for MALD. Additional markers can be added to this MALD map by utilization of the rapidly growing single-nucleotide-polymorphism databases and the literature, to achieve a 3-10-cM scanning scale. The map will be useful for studies of diseases, including prostate and breast cancer, diabetes, hypertension, and end-stage renal disease, that have large differences in incidence between the founding populations of either Hispanics or African Americans.

Black or African American↗
PubMed2005

Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study.

U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.

Black or African American↗
PubMed1995

Physicochemical stability of total nutrient admixtures.

The effect of six independent factors on the stability of i.v. nutritional emulsions was studied. Forty-five i.v. nutritional admixtures were prepared, each containing the following: (1) amino acids (range, 2.5-7%), (2) hydrated glucose (range, 5-20%), (3) lipid emulsion (range, 2-5%), (4) monovalent cations (range, 0-150 meq/L), (5) divalent cations (range, 4-20 meq/L), and (6) trivalent cations (range, 0-10 mg of elemental iron/L). Stability assessments included particle-size analysis, pH determination, and visual inspection. Sizing and counting of fat particles was achieved by using light obscuration and dynamic light scatter methods. Light obscuration and visual assessments were performed at 0, 6, 12, 24, and 30 hours. Dynamic light scatter and pH determinations were performed at 0 and 30 hours. Multiple stepwise regression analysis revealed that trivalent cation concentration was the only variable that affected the stability of nutritional emulsions (p < 0.00001), accounting for approximately 60% of the potentially dangerous increases in fat particle sizes observed. In addition, a percentage of large fat particles (> 5 microns in diameter) greater than 0.4% was associated with unstable emulsions. However, this instability was visibly evident only 65% of the time. Changes in mean globule diameter, cream-layer thickness, and pH did not reveal instability in these emulsions. Emulsions in which > 0.4% of the initial fat concentration consists of particles of > 5 microns in diameter are likely to become unstable. Of the six factors studied, the trivalent cation in iron dextran was most disruptive to lipid-based parenteral nutrient admixtures.

Amino Acids↗
PubMed2025

HAP-SAMPLE2: data-based resampling for association studies with admixture.

MOTIVATION: HAP-SAMPLE2 extends the functionality of the original HAP-SAMPLE tool for simulating genotype-phenotype data, now with features to handle population admixture and rare variant analysis. It allows users to define parameters such as disease prevalence and allele effect sizes for both common and rare variant simulations. RESULTS: HAP-SAMPLE2 provides an efficient means for simulating complex datasets, suitable for large-scale projects like the 1000 Genomes Project. Its capabilities for population admixture allow users to create admixed populations or preserve substructures while introducing novel variation through artificial recombination. Additionally, the tool supports burden testing for rare variants using fixed and Madsen-Browning weighting schemes. AVAILABILITY AND IMPLEMENTATION: The software, along with a detailed vignette, is available on GitHub: https://github.com/M3dical/HAPSAMPLE2.

Software↗
PubMed1975

The magnitude of air admixture with a jet device in paediatric anaesthesia.

The admixture of air in inspired gas with a paediatric insufflation system based on a gas jet has been investigated. During anaesthesia with spontaneous ventilation 1% of air per kg body weight was found in tracheal gas samples. A venturi effect was virtually absent even at high jet flows, which suggests that artificial ventilation prevents air admixture.

Air↗
PubMed1989

Effects of lung surgery and one-lung ventilation on pulmonary arterial pressure, venous admixture and immediate postoperative lung function.

We studied 17 patients, with unilateral lesions in lung or thoracic wall, during thoracotomy performed in the full lateral position. Balanced anaesthesia was used with pethidine and 50% nitrous oxide, in oxygen. The procedure included a period of one-lung ventilation (OLV). Haemodynamic and gas exchange measurements were performed before and after pleurotomy, during OLV, after re-expansion of the lung and after closure of the thoracic wall. The function of each lung was assessed separately during the first and last stages. Mean venous admixture was 9-12% before and after OLV and 31% during OLV. There was a positive correlation between venous admixture and pulmonary arterial pressure during OLV. End-tidal PCO2, carbon dioxide elimination and compliance of the operated side were reduced significantly at the end of the procedure; this is consistent with reduced blood flow and increased water content in that lung.

Anesthesia, General↗
PubMed2002

Effect of different pulses of nitric oxide on venous admixture in the anaesthetized horse.

BACKGROUND: Dependent atelectatic lung areas open towards the end of inspiration when the lung opening pressure increases, and recollapse during expiration. We hypothesized that inhaled nitric oxide (NO) counteracts hypoxic vasoconstriction in these collapsing lung areas, resulting in increased pulmonary shunt perfusion. METHODS: We administered NO as a pulse and varied the pulse timing during inspiration in equine anaesthesia, where atelectasis develops regularly. Six spontaneously breathing standard breed trotters were studied under isoflurane anaesthesia in lateral recumbency. NO pulsed into the first 30% of inspiration (group NOp1) was assumed to affect open lung areas. To cover more open lung areas NO was then pulsed into the first 60% of inspiration (group NOp2). In a third group, administration between 50 and 80% of inspiration was aimed at the intermittently opening lung areas (group NOp3). RESULTS: With NOp1, venous admixture decreased by 8 (2)% (mean (SEM), P=0.045) and with NOp2 by 10 (1)% (P=0.01). With NOp3, venous admixture reduction was insignificant. CONCLUSIONS: Pulsed administration of NO in early inspiration is optimal in reducing right to left vascular shunt in atelectatic equine lung. This reduction is positively correlated with the magnitude of the initial shunt. With administration in early inspiration, NO is mostly taken up by the lung. This prevents NO accumulation and NO2 formation in rebreathing circuits. These findings may be important in humans when atelectasis occurs increasingly with overweight and age during anaesthesia, but also in postoperative intensive care and in ARDS.

Anesthesia, Inhalation↗
PubMed2002

Variation of venous admixture, SF6 shunt, PaO2, and the PaO2/FIO2 ratio with FIO2.

BACKGROUND: Measures of impairment of oxygenation can be affected by the inspired oxygen fraction. METHODS: We used a mathematical model of an inhomogenous lung to predict the effect of increasing inspired oxygen concentration (FIO2) on: (1) venous admixture (Qva/Qt); (2) arterial oxygen partial pressure (PaO2); (3) the PaO2/FIO2 index of hypoxaemia; and (4) sulphur hexafluoride (SF6) retention (often taken to be true right-to-left shunt). This model predicts whether or not atelectasis will occur. RESULTS: For lungs with regions of low V/Q, increasing the inspired oxygen concentration can cause these regions to collapse. In the absence of atelectasis, the model predicts that Qva/Qt will decrease and arterial oxygen partial pressure increase as FIO2 is increased. However, when atelectasis occurs, Qva/Qt rises to a constant value, whilst PaO2 falls at first, but then begins to rise again, with increasing FIO2. The SF6 retention increased markedly in some cases at high FIO2. CONCLUSIONS: Venous admixture will estimate true right-to-left shunt at high FIO2, even when oxygen consumption is raised. This model can explain the way that the Pa/Fl ratio changes with increasing inspired oxygen concentration.

Computer Simulation↗
PubMed1999

Antifungal activity of amphotericin B-lipid admixtures in experimental systemic candidosis in naive mice.

We have shown previously that admixtures of amphotericin B (AMB) and Intralipid (AMB-IL) obtained by vigorous and prolonged agitation are stable and can be standardized. These preparations exhibited in-vitro activity against various Candida spp., and had significantly lower toxicity. The present study was undertaken to evaluate the activity of AMB-IL admixtures in vivo in comparison with the conventional formulation of AMB (Fungizone), using a murine model of experimental systemic candidosis. ICR female mice (4-6 weeks old) were injected iv with 5 x 10(4) Candida albicans CBS 562. The animals developed a lethal infection (100%) within 10 days. Systemic candidosis was demonstrated by the presence of fungal elements in kidneys and spleen tissue, and by enumeration of cfu of Candida in the tissue homogenates. AMB-IL or AMB was administered iv 48 h post-Candida inoculation for 5 consecutive days. Four experiments with 108 mice treated with AMB 5 x 0.4 mg/kg and followed up for 6 weeks, showed that the mean survival percentages at the end of the experiment were 0, 24.9 and 52.5% for the untreated group, conventional AMB-treated and AMB-IL-treated groups, respectively. The mean survival time (MST) was 7.4, 25 and 30 days for the untreated, conventional AMB-treated and AMB-IL-treated groups, respectively. Use of increased doses of AMB showed that conventional AMB at doses greater than 5 x 1 mg/kg caused immediate animal death. AMB-IL was used at doses of AMB up to 5 x 2 mg/kg. Experiments with 104 mice revealed that the mean survival percentage at the end of the experiment was 0, 34.5, 58.6 and 97% for the untreated, conventional AMB-treated (5 x 1 mg/kg), AMB-IL-1-treated (5 x 1 mg/kg) and AMB-IL-2-treated (5 x 2 mg/kg) groups, respectively. The MST was 7, 27.8, 34.8 and 41.4 days for the untreated, conventional AMB-treated, AMB-IL-1-treated and AMB-IL-2-treated groups, respectively. The results of this study reveal that AMB-IL is significantly more effective in treating systemic murine candidosis than conventional AMB.

Amphotericin B↗
PubMed1998

Inferring admixture proportions from molecular data.

We derive here two new estimators of admixture proportions based on a coalescent approach that explicitly takes into account molecular information as well as gene frequencies. These estimators can be applied to any type of molecular data (such as DNA sequences, restriction fragment length polymorphisms [RFLPs], or microsatellite data) for which the extent of molecular diversity is related to coalescent times. Monte Carlo simulation studies are used to analyze the behavior of our estimators. We show that one of them (mY) appears suitable for estimating admixture from molecular data because of its absence of bias and relatively low variance. We then compare it to two conventional estimators that are based on gene frequencies. mY proves to be less biased than conventional estimators over a wide range of situations and especially for microsatellite data. However, its variance is larger than that of conventional estimators when parental populations are not very differentiated. The variance of mY becomes smaller than that of conventional estimators only if parental populations have been kept separated for about N generations and if the mutation rate is high. Simulations also show that several loci should always be studied to achieve a drastic reduction of variance and that, for microsatellite data, the mean square error of mY rapidly becomes smaller than that of conventional estimators if enough loci are surveyed. We apply our new estimator to the case of admixed wolflike Canid populations tested for microsatellite data.

Animals↗