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B S Weir

Publications and source records attributed to B S Weir.

At least 37 records · Page 2Linked to original sources
PubMed2000

Conditional genotypic probabilities for microsatellite loci.

Modern forensic DNA profiles are constructed using microsatellites, short tandem repeats of 2-5 bases. In the absence of genetic data on a crime-specific subpopulation, one tool for evaluating profile evidence is the match probability. The match probability is the conditional probability that a random person would have the profile of interest given that the suspect has it and that these people are different members of the same subpopulation. One issue in evaluating the match probability is population differentiation, which can induce coancestry among subpopulation members. Forensic assessments that ignore coancestry typically overstate the strength of evidence against the suspect. Theory has been developed to account for coancestry; assumptions include a steady-state population and a mutation model in which the allelic state after a mutation event is independent of the prior state. Under these assumptions, the joint allelic probabilities within a subpopulation may be approximated by the moments of a Dirichlet distribution. We investigate the adequacy of this approximation for profiled loci that mutate according to a generalized stepwise model. Simulations suggest that the Dirichlet theory can still overstate the evidence against a suspect with a common microsatellite genotype. However, Dirichlet-based estimators were less biased than the product-rule estimator, which ignores coancestry.

Alleles↗
PubMed1999

Bayesian statistics in genetics: a guide for the uninitiated.

Statistical analyses are used in many fields of genetic research. Most geneticists are taught classical statistics, which includes hypothesis testing, estimation and the construction of confidence intervals; this framework has proved more than satisfactory in many ways. What does a Bayesian framework have to offer geneticists? Its utility lies in offering a more direct approach to some questions and the incorporation of prior information. It can also provide a more straightforward interpretation of results. The utility of a Bayesian perspective, especially for complex problems, is becoming increasingly clear to the statistics community; geneticists are also finding this framework useful and are increasingly utilizing the power of this approach.

Bayes Theorem↗
PubMed1999

A classical setting for associations between markers and loci affecting quantitative traits.

We examine the relationships between a genetic marker and a locus affecting a quantitative trait by decomposing the genetic effects of the marker locus into additive and dominance effects under a classical genetic model. We discuss the structure of the associations between the marker and the trait locus, paying attention to non-random union of gametes, multiple alleles at the marker and trait loci, and non-additivity of allelic effects at the trait locus. We consider that this greater-than-usual level of generality leads to additional insights, in a way reminiscent of Cockerham's decomposition of genetic variance into five terms: three terms in addition to the usual additive and dominance terms. Using our framework, we examine several common tests of association between a marker and a trait.

Animals↗
PubMed1999

Interpreting DNA mixtures in structured populations.

DNA profiles from multiple-contributor samples are interpreted by comparing the probabilities of the profiles under alternative propositions. The propositions may specify some known contributors to the sample and may also specify a number of unknown contributors. The probability of the alleles carried by the set of people, known or unknown, depends on the allelic frequencies and also upon any relationships among the people. Membership of the same subpopulation implies a relationship from a shared evolutionary history, and this effect has been incorporated into the probabilities. This acknowledgment of the effects of population structure requires account to be taken of all people in a subpopulation who are typed, whether or not they contributed to the sample.

Alleles↗
PubMed1998

Marker selection for the transmission/disequilibrium test, in recently admixed populations.

Recent admixture between genetically differentiated populations can result in high levels of association between alleles at loci that are <=10 cM apart. The transmission/disequilibrium test (TDT) proposed by Spielman et al. (1993) can be a powerful test of linkage between disease and marker loci in the presence of association and therefore could be a useful test of linkage in admixed populations. The degree of association between alleles at two loci depends on the differences in allele frequencies, at the two loci, in the founding populations; therefore, the choice of marker is important. For a multiallelic marker, one strategy that may improve the power of the TDT is to group marker alleles within a locus, on the basis of information about the founding populations and the admixed population, thereby collapsing the marker into one with fewer alleles. We have examined the consequences of collapsing a microsatellite into a two-allele marker, when two founding populations are assumed for the admixed population, and have found that if there is random mating in the admixed population, then typically there is a collapsing for which the power of the TDT is greater than that for the original microsatellite marker. A method is presented for finding the optimal collapsing that has minimal dependence on the disease and that uses estimates either of marker allele frequencies in the two founding populations or of marker allele frequencies in the current, admixed population and in one of the founding populations. Furthermore, this optimal collapsing is not always the collapsing with the largest difference in allele frequencies in the founding populations. To demonstrate this strategy, we considered a recent data set, published previously, that provides frequency estimates for 30 microsatellites in 13 populations.

Alleles↗
PubMed1998

A comparative study of sibship tests of linkage and/or association.

Population-based tests of association have used data from either case-control studies or studies based on trios (affected child and parents). Case-control studies are more prone to false-positive results caused by inappropriate controls, which can occur if, for example, there is population admixture or stratification. An advantage of family-based tests is that cases and controls are well matched, but parental data may not always be available, especially for late-onset diseases. Three recent family-based tests of association and linkage utilize unaffected siblings as surrogates for untyped parents. In this paper, we propose an extension of one of these tests. We describe and compare the four tests in the context of a complex disease for both biallelic and multiallelic markers, as well as for sibships of different sizes. We also examine the consequences of having some parental data in the sample.

Alleles↗
PubMed1998

Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus.

We review and extend a recent suggestion that fine-scale localization of a disease-susceptibility locus for a complex disease be done on the basis of deviations from Hardy-Weinberg equilibrium among affected individuals. This deviation is driven by linkage disequilibrium between disease and marker loci in the whole population and requires a heterogeneous genetic basis for the disease. A finding of marker-locus Hardy-Weinberg disequilibrium therefore implies disease heterogeneity and marker-disease linkage disequilibrium. Although a lack of departure of Hardy-Weinberg disequilibrium at marker loci implies that disease susceptibilityweighted linkage disequilibria are zero, given disease heterogeneity, it does not follow that the usual measures of linkage disequilibrium are zero. For disease-susceptibility loci with more than two alleles, therefore, care is needed in the drawing of inferences from marker Hardy-Weinberg disequilibria.

Alleles↗
PubMed1998

A Bayesian characterization of Hardy-Weinberg disequilibrium.

A Bayesian method for determining if there are large departures from independence between pairs of alleles at a locus, Hardy-Weinberg equilibrium (HWE), is presented. We endorse the view that a population will never be exactly in HWE and that there will be occasions when there is a need for an alternative to the usual hypothesis-testing setting. Bayesian methods provide such an alternative, and our approach differs from previous Bayesian treatments in using the disequilibrium and inbreeding coefficient parameterizations. These are easily interpretable but may be less mathematically tractable than other parameterizations. We examined the posterior distributions of our parameters for evidence that departures from HWE were large. For either parameterization, when a conjugate prior was used, the prior probability for small departures was itself small, i.e., the prior was weighted against small departures from independence. We could avoid this uneven weighting by using a step prior which gave equal weighting to both small and large departures from HWE. In most cases, the Bayesian methodology makes it clear that there are not enough data to draw a conclusion.

Alleles↗
PubMed1997

Tests for linkage and association in nuclear families.

The transmission/disequilibrium test (TDT) originally was introduced to test for linkage between a genetic marker and a disease-susceptibility locus, in the presence of association. Recently, the TDT has been used to test for association in the presence of linkage. The motivation for this is that linkage analysis typically identifies large candidate regions, and further refinement is necessary before a search for the disease gene is begun, on the molecular level. Evidence of association and linkage may indicate which markers in the region are closest to a disease locus. As a test of linkage, transmissions from heterozygous parents to all of their affected children can be included in the TDT; however, the TDT is a valid chi2 test of association only if transmissions to unrelated affected children are used in the analysis. If the sample contains independent nuclear families with multiple affected children, then one procedure that has been used to test for association is to select randomly a single affected child from each sibship and to apply the TDT to those data. As an alternative, we propose two statistics that use data from all of the affected children. The statistics give valid chi2 tests of the null hypothesis of no association or no linkage and generally are more powerful than the TDT with a single, randomly chosen, affected child from each family.

Alleles↗
PubMed1997

Hardy-Weinberg testing for continuous data.

Estimation of allelic and genotypic distributions for continuous data using kernel density estimation is discussed and illustrated for some variable number of tandem repeat data. These kernel density estimates provide a useful representation of data when only some of the many variants at a locus are present in a sample. Two Hardy-Weinberg test procedures are introduced for continuous data: a continuous chi-square test with test statistic T(CCS) and a test based on Hellinger's distance with test statistic T(HD). Simulations are used to compare the powers of these tests to each other and to the powers of a test of intraclass correlation T(IC), as well as to the power of Fisher's exact test T(FET) applied to discretized data. Results indicate that the power of T(CCS) is better than that of T(HD), but neither is as powerful as T(FET). The intraclass correlation test does not perform as well as the other tests examined in this article.

Alleles↗
PubMed1997

Power studies for the transmission/disequilibrium tests with multiple alleles.

Case-control studies compare marker-allele distributions in affected and unaffected individuals, and significant results suggest linkage but may simply reflect population structure. For markers with m alleles (m > or = 2), a McNemar-like statistic, I, estimates the level of population association between marker and disease loci. To test for linkage after significant case-control tests, within-family tests are performed. These operate on the contingency table, with i, jth element equal to the number of parents that transmit marker allele Mi and do not transmit marker allele Mi to an affected offspring. The dimension of the table is the number of alleles at the marker locus. Three test statistics have recently been proposed in the literature: Tc compares symmetric pairs of cells (i, j) and (j, i), Tm compares row and column totals for the same marker allele, and a likelihood ratio statistic Tl uses all the cells in the table. In addition, we consider a new statistic, Tmhet, that uses only the heterozygous parents and is approximately chi2 with (m - 1) df. We use a Monte Carlo test to guarantee valid tests and to demonstrate the inferiority of Tc and the equality of Tm and Tl in terms of power. The power of the Tmhet test is close but not always equal to the power of the Tm test. We also show that under the alternative hypothesis of linkage, Tm is approximately noncentral chi2 with (m - 1) df and noncentrality parameter 2NT(1 - 2theta)2I*, when data on single affecteds in NT families are used. If the disease has a low population frequency, then I* is estimated using the case-control statistic I. This offers a basis for choosing sample size, or choosing a marker system.

Alleles↗
PubMed1997

Interpreting DNA mixtures.

The interpretation of mixed DNA stains is explained in the context of likelihood ratios. The probabilities for the mixed-stain profile are evaluated under alternative explanations that specify the numbers of contributors and the profiles of any known contributors. Interpretations based simply on the frequencies with which random members of a population would not be excluded from a mixed-stain profile do not make use of all the information, and may overstate the strength of the evidence against included people. The effects of the numbers of contributors depends on whether all the alleles at a locus are present in the mixed stain. A general equation is given to allow likelihood ratios to be calculated, and includes the "2p" modification suggested by the 1996 NRC report. This modification is not always conservative. A computer program to perform calculations is available.

Alleles↗
PubMed1996

Statistical analysis of a large file of data from STR profiles of British Caucasians to support forensic casework.

Data from nearly 2500 British Caucasians, profiled using an STR quadruplex, have been analysed. The data came from several laboratories and represent samples from different geographical distributions. Analysis of the combined files shows that previous reports of failed independence tests were the results of sampling effects. A further convincing proof is given of the robustness of the statistical methods used to estimate evidential value in casework. Comparisons between different samples show that regional effects between Scotland and the South of England have no importance from the forensic viewpoint.

Adult↗
PubMed1996

Mixed model approaches for diallel analysis based on a bio-model.

A MINQUE(1) procedure, which is minimum norm quadratic unbiased estimation (MINQUE) method with 1 for all the prior values, is suggested for estimating variance and covariance components in a bio-model for diallel crosses. Unbiasedness and efficiency of estimation were compared for MINQUE(1), restricted maximum likelihood (REML) and MINQUE theta which has parameter values for the prior values. MINQUE(1) is almost as efficient as MINQUE theta for unbiased estimation of genetic variance and covariance components. The bio-model is efficient and robust for estimating variance and covariance components for maternal and paternal effects as well as for nuclear effects. A procedure of adjusted unbiased prediction (AUP) is proposed for predicting random genetic effects in the bio-model. The jack-knife procedure is suggested for estimation of sampling variances of estimated variance and covariance components and of predicted genetic effects. Worked examples are given for estimation of variance and covariance components and for prediction of genetic merits.

Alleles↗
PubMed1996

A genome-wide survey of hybrid incompatibility factors by the introgression of marked segments of Drosophila mauritiana chromosomes into Drosophila simulans.

In hybrids between Drosophila simulans and D. mauritiana, males are sterile and females are fertile, in compliance with HALDANE's rule. The genetic basis of this phenomenon was investigated by introgression of segments of the mauritiana genome into a simulans background. A total of 87 positions throughout the mauritiana genome were marked with P-element insertions and replicate introgressions were made by repeated backcrossing to simulans for 15 generations. The fraction of hemizgyous X chromosomal introgressions that are male sterile is approximately 50% greater than the fraction of homozygous autosomal segments. This result suggests that male sterility factors have evolved at a higher rate on the X, but chromosomal differences in segment length cannot be ruled out. The fraction of homozygous autosomal introgression that are male sterile is several times greater than the fraction that are either female sterile or inviable. This observation strongly indicates that male sterility factors have evolved more rapidly than either female sterility or inviability factors. These results, combined with previous work on these and other species, suggest that HALDANE's rule has at least two causes: recessivity of incompatibility factors and differential accumulation of sterility factors affecting males and females.

Animals↗
PubMed1996

Establishing the robustness of short-tandem-repeat statistics for forensic applications.

Before the introduction of a four-locus multiplex short-tandem-repeat (STR) system into casework, an extensive series of tests were carried out to determine robust procedures for assessing the evidential value of a match between crime and suspect samples. Twelve databases were analyzed from the three main ethnic groups encountered in casework in the United Kingdom: Caucasians, Afro-Caribbeans, and Asians from the Indian subcontinent. Independence tests resulted in a number of significant results, and the impact that these might have on forensic casework was investigated. It is demonstrated that previously published methods provide a simple procedure for correcting allele frequencies--and that this leads to conservative casework estimates of evidential value.

Alleles↗