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Biomedical subjects

P Donnelly

Publications and source records attributed to P Donnelly.

At least 19 recordsLinked to original sources
PubMed2000

Association mapping in structured populations.

The use, in association studies, of the forthcoming dense genomewide collection of single-nucleotide polymorphisms (SNPs) has been heralded as a potential breakthrough in the study of the genetic basis of common complex disorders. A serious problem with association mapping is that population structure can lead to spurious associations between a candidate marker and a phenotype. One common solution has been to abandon case-control studies in favor of family-based tests of association, such as the transmission/disequilibrium test (TDT), but this comes at a considerable cost in the need to collect DNA from close relatives of affected individuals. In this article we describe a novel, statistically valid, method for case-control association studies in structured populations. Our method uses a set of unlinked genetic markers to infer details of population structure, and to estimate the ancestry of sampled individuals, before using this information to test for associations within subpopulations. It provides power comparable with the TDT in many settings and may substantially outperform it if there are conflicting associations in different subpopulations.

Alleles↗
PubMed1995

Rugby injuries.

Explore the source record for details and available documents.

Adolescent↗
PubMed1995

Match probability calculations for multi-locus DNA profiles.

The paper considers aspects of the match probability calculation for multi-locus DNA profiles and a related calculation which aims to assess the probability that a pair of profiles is concordant for the presence and absence of bands. It is suggested that levels of allelism and linkage for multi-locus profiles may be higher than reported in previous studies, and that comparison of bandsharing values between different studies is problematic. Our view is that the independence assumptions which underpin the calculations have not been established. The effect of ignoring (local) heterogeneities in band frequencies may be non-conservative. Concerns thus raised about the match probability calculation could be important in practical casework. The speculative nature of some aspects of the concordance probability calculation would seem to render it inappropriate for use in court.

Alleles↗
PubMed1995

Nonindependence of matches at different loci in DNA profiles: quantifying the effect of close relatives on the match probability.

In comparing a particular DNA profile with that from an unknown (but distinct) individual, matches at different loci between the profiles will not be independent, even in a randomly mating population, because of the presence in the population of relatives of the individuals. The paper contains a theoretical analysis of the extent of this effect on the match probability, for profiling techniques which separately probe different loci. Naive calculation using the product rule could substantially understate the match probability. Past a certain point, the testing of additional loci provides no more information than would be available in discriminating between sibs. The correlation effect described here would be unimportant in criminal casework if close relatives of the suspect, and in particular full-sibs, were excluded as possible culprits. In the absence of such exclusions the current practice of effectively ignoring such relatives in presenting match probabilities could be extremely prejudicial to a suspect, even in cases in which there is no direct evidence to incriminate his/her relatives.

Alleles↗
PubMed1995

Mapping of a gene for long QT syndrome to chromosome 4q25-27.

Long QT syndrome (LQTS) is a heterogeneous inherited disorder causing syncope and sudden death from ventricular arrhythmias. A first locus for this disorder was mapped to chromosome 11p15.5. However, locus heterogeneity has been demonstrated in several families, and two other loci have recently been located on chromosomes 7q35-36 and 3p21-24. We used linkage analysis to map the locus in a 65-member family in which LQTS was associated with more marked sinus bradycardia than usual, leading to sinus node dysfunction. Linkage to chromosome 11p15.5, 7q35-36, or 3p21-24 was excluded. Positive linkage was obtained for markers located on chromosome 4q25-27. A maximal LOD score of 7.05 was found for marker D4S402. The identification of a fourth locus for LQTS confirms its genetic heterogeneity. Locus 4q25-27 is associated with a peculiar phenotype within the LQTS entity.

Chromosome Mapping↗
PubMed1994

Pairwise comparisons of mitochondrial DNA sequences in subdivided populations and implications for early human evolution.

We consider the effect on the distribution of pairwise differences between mitochondrial DNA sequences of the incorporation into the underlying population genetics model of two particular effects that seem realistic for human populations. The first is that the population size was roughly constant before growing to its current level. The second is that the population is geographically subdivided rather than panmictic. In each case these features tend to encourage multimodal distributions of pairwise differences, in contrast to existing, unimodal datasets. We argue that population genetics models currently used to analyze such data may thus fail to reflect important features of human mitochondrial DNA evolution. These may include selection on the mitochondrial genome, more realistic mutation mechanisms, or special population or migration dynamics. Particularly in view of the variability inherent in the single available human mitochondrial genealogy, it is argued that until these effects are better understood, inferences from such data should be rather cautious.

Animals↗
PubMed1993

Idarubicin-related side effects in recipients of T-cell-depleted allogeneic bone marrow transplants are schedule dependent.

The influence of three different dosage schedules of anthracycline (idarubicin or daunorubicin)-intensified preparative therapy prior to T-cell-depleted allogeneic bone marrow transplantation (BMT) on (1) the severity and duration of oral toxicity (mucositis), (2) the duration of bone marrow aplasia, and (3) overall survival, relapse, and disease-free survival was studied in 99 BMT patients with standard- or high-risk hematologic malignancies. A further 146 patients who did not receive the anthracycline-intensified conditioning served as (historic) controls. All patients received cyclophosphamide (total dose, 120 mg/kg) on days -6 and -5 and total body irradiation on days -2 and -1 prior to BMT. The 99 patients who received the anthracycline-intensified preparative regimen were given either idarubicin (total dose, 42 mg/m2; n = 88) or daunorubicin (total dose, 156 mg/m2; n = 11) by continuous intravenous infusion between days -7 and -1 prior to BMT in 59 cases (cohort 1), on days -8 and -7 in 17 cases (cohort 2), and on days -12 and -11 in 23 cases (cohort 3). The occurrence of severe oral mucositis and delayed bone marrow recovery was schedule dependent, being substantially lower with earlier administration of the anthracycline-intensified regimen on days -12 and -11 before BMT (cohort 3), in comparison with later administration (cohorts 1 and 2). Plasma drug and metabolite concentrations were measured in 11 patients who received idarubicin. At the time of allogeneic bone marrow infusion (day 0), patients in cohorts 1 and 2 had plasma concentrations of idarubicin and idarubicinol (its active metabolite) in the range of in vitro cytotoxicity. However, in cohort 3, plasma concentrations on day 0 were much lower, which correlated with the lower maximum intensity and shorter duration of mucositis in these patients. In terms of overall survival, relapse rate, and disease-free survival in standard-risk patients, the anthracycline-intensified regimen proved to be very effective. Transplant-related mortality was 25% in the anthracycline group compared with 32% in the controls. The probability of relapse also was significantly less in the anthracycline group in comparison with controls (17% v 46%; P < .001), and the probabilities of long-term overall and disease-free survival were significantly greater (71% v 37% [P < .01] and 63% v 32% [P < .01], respectively). Only three patients in the idarubicin group experienced cardiotoxicity (one in each cohort); the causative relationship with anthracyclines was considered likely in one, possible in one, and doubtful in the third.

Adolescent↗
PubMed1992

Do Eve's alleles live on?

Consider a random sample of genes at a locus, drawn from a population evolving according to the infinitely many, neutral, alleles model. The sample will have a most recent common ancestor gene, which we shall call 'Eve'. The probability distribution, for the number of genes of oldest allelic type in a sample, is known and has a neat form. Rather less is known about the distribution for the number of genes in the sample which are of the same allelic type as Eve possessed. If the latter number is positive, then these genes are automatically of the oldest type in the sample. But Eve may have no non-mutant descendants in the sample; then, the oldest allele will be a mutant arising in a line of descent after Eve. The paper studies the number of non-mutant descendants from Eve, its distribution and moments. It seems that there may be few neat results. In large samples, the proportion of genes of Eve's type has an approximate beta-like density, together with a discrete probability atom at zero, if the mutation rate parameter is low. Extinction of the allele of even the population's common ancestor is possible, but not certain, and bounds are obtained for its probability. Some comments are made about the applications and implications of the results for human mitochondrial DNA.

Alleles↗
PubMed1991

Donor-recipient age difference--an independent risk factor in cyclosporin-treated renal transplant recipients.

Whilst HLA matching is routine in renal transplantation the possible benefits of matching donor to recipient age have not been previously explored. The simultaneous effect on graft survival of donor and recipient age was therefore investigated for 274 consecutive first cadaver transplant recipients treated by cyclosporin immunosuppression in two centres. The overall graft survival was 77%, and was not significantly different between the two centres. Individually there was no significant effect of donor or recipient age but taken together, the difference in age significantly affected graft survival (P less than 0.01) regardless of the mode of failure. The 1-year graft survival for all failures was 66.2% when the donor was 5 or more years older. 84.5% when the donor was 5 or more years younger and 71.7% when the donor was within 5 years of the recipient's age. Multivariate analysis, taking into account other variables (HLA matching, dialysis time and type, donor/recipient sex, local/imported kidneys, sensitivity, operation time, total ischaemic time, pre-operative transfusions) indicated that age difference was the single most important variable (P less than 0.01). The only other important covariate risk factor in improving graft survival was HLA-DR matching (P less than 0.05). Donor-recipient age difference is a potentially important recipient selection criterion in cyclosporin-treated renal transplant patients.

Adolescent↗
PubMed1991

A review of the racial differences in the lung function of normal Caucasian, Chinese and Indian subjects.

In the clinic, predicted normal values are widely used for routine assessments and, therefore, it is important that the noted differences in lung volumes between the races are recognized. Further epidemiological studies, using comparative methods and standard statistical techniques, are essential in order to quantify apparent differences between the races and to standardize normal values for race, especially with regard to age, with greater accuracy.

Adult↗