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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↗
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↗
PubMed1990

A distinct HLA-DRw8 haplotype characterizes patients with juvenile rheumatoid arthritis.

We studied the first domain of the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci of 67 HLA-DRw8-positive Caucasians including 43 with early-onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA, alternatively known as early-onset pauciarticular juvenile chronic arthritis). Serology, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR) oligotyping revealed that 62, including all the EOPA-JRA patients, carried the HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype. Approximately one-fifth of the controls carried atypical HLA-DRB1, HLA-DQA1, and/or HLA-DQB1 loci on their HLA-DRw8 haplotype confirmed by family studies. DNA sequences of HLA-DRB1, DQA1, and DQB1 alleles in patients and controls were identical to those previously reported. Disease association studies in 113 EOPA-JRA patients and 207 controls unselected for HLA-DRw8 revealed that the HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype was associated with a higher relative risk (RR) for disease (RR = 12.8, chi 2 = 48.8, P less than 10(-4)) than was the serologically defined presence of HLA-DRw8 (RR = 8, chi 2 = 39, P less than 10(-4)). Further analysis suggested that the DQ genes on HLA-DRw8 haplotypes are as likely as the DR genes to contribute to the pathogenesis of EOPA-JRA. This study increases to five the number of HLA-DR/DQ haplotypes identified in HLA-DRw8 Caucasians.

Arthritis, Juvenile↗
PubMed1990

Amikacin plus piperacillin versus ceftazidime as initial therapy in granulocytopenic patients with presumed bacteremia.

69 febrile granulocytopenic episodes without an initial focus of infection were assessed for empiric treatment either with high-dose amikacin plus piperacillin or ceftazidime. 90% of patients in each group survived the granulocytopenic episode; 15 (44 +/- 17%) episodes treated with the combination and 23 (66 +/- 16%) given ceftazidime responded without any modification of initial therapy and half defervesced within 72 h. Persistent fever was the most frequent reason for altering treatment which was done empirically in 90% of cases, but two-thirds of patients required further treatment modification. An infectious focus mainly involving the lung developed during granulocytopenia in 21 patients (30%), of which 17 occurred during antimicrobial therapy. Only 1 infection was shown to be due to bacteria, while 7 were due to fungi. Amikacin levels were similar to those expected following a normal dose (mean peak of 34.7 and mean trough of 12.6 mg/l). Therapy with the combination resulted in a higher serum creatinine (p less than 0.001) and a lower potassium level (p less than 0.001) in comparison with monotherapy. Potassium supplementation was required in 45 +/- 17% of patients given the combination compared with only 4 +/- 7% of those treated with ceftazidime. While both regimens appeared to be equally effective as initial therapy, the need for modification was high in both patient groups. Monotherapy being both simpler to administer and less toxic seems therefore to be the logical choice although the period of empiric therapy must be fully exploited in order to improve diagnosis and therefore antimicrobial management.

Adolescent↗
PubMed1989

The oxygen delivery characteristics of the Hudson Oxy-one face mask.

The inspired oxygen fraction (FIO2) delivered by the Hudson Oxy-one face mask was measured under changing conditions of ventilation, oxygen flow rate to mask, and mask fit. A single trained subject sat in a body plethysmograph to measure ventilation and breathed at a constant rate of 15 per minute at three different tidal volumes, of approximately 0.3, 0.6, and 1.2 litres, from the mouthpiece in the plethysmograph. The Oxy-one face mask was fitted to a plaster-of-Paris face model on the outside of the plethysmograph in a loose and then in a tight fashion. Oxygen concentration was continuously monitored from a point in the metal tube connecting the face model to the mouthpiece. The tightly fitting mask demonstrated an orderly reduction in FIO2 as ventilation increased and oxygen flow rate to the mask decreased. The mean FIO2 at a ventilation of 4.5 l.min-1 and 8 l.min-1 oxygen flow was 78% and this fell to 27% at a ventilation of 16 l.min-1 and oxygen flow of 2 l.min-1. The loosely fitting mask demonstrated larger SD of measurements and lower mean maximum FIO2 values of 46 to 49% and these fell in an irregular fashion to similar minimum values as ventilation increased and oxygen flow decreased. Although the precise definition of the FIO2 for each breath from the changing concentration during each inspiration was not possible, these results indicate that FIO2 changes in a predictable way as a function of ventilation and oxygen flow, if the mask is close fitting. This method could be conveniently used to study other oxygen delivery systems.

Evaluation Studies as Topic↗
PubMed1987

The population genealogy of the infinitely--many neutral alleles model.

A process analogous to Kingman's coalescent is introduced to describe the genealogy of populations evolving according to the infinitely- many neutral alleles model. The process records population frequencies in old and new classes, and labels the new classes in order of decreasing age. Its marginal distribution is characterized in a form which is amenable to explicit calculations and the transition densities of the associated K-allele models follow readily from this representation.

Alleles↗
PubMed1987

Specific and nonspecific immunoregulatory factors and renal transplantation.

From a study population of 208 consecutive first cadaver renal transplant recipients a proportional hazard model was used to simultaneously quantify the role in graft failure of matching for specific HLA antigens and constitutional factors (age, sex, duration of dialysis (Dt), and pre- (PTr) and peri-(PerTr) operative transfusions) that influence nonspecific immune response. A comparison was also made of graft survival in patients treated by the two principal methods of dialysis, hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). The advisability of including nonimmunological failures in studies of graft survival was also considered. The analysis indicated that factors influencing a patient's innate nonspecific immune response (e.g., Dt and PTr) are important determinants of graft survival and should be taken into account when considering matching for specific HLA-B or DR antigens prior to transplantation. While there was no overall effect of dialysis type on graft survival, the influence of other risk factors depended on the method of dialysis. Failure to identify and exclude graft loss for nonimmunological reasons can give rise to misleading conclusions in analysis of immunoregulatory factors in organ transplantation.

Blood Transfusion↗
PubMed1986

Partition structures, Polya urns, the Ewens sampling formula, and the ages of alleles.

It has recently been shown that the Ewens sampling formula may be generated by a Polya-like urn model. A genealogical proof of this result equates the labelling of balls in the urn to the partition by age of alleles in the sample. This urn construction is shown to be equivalent to the construction of Kingman (Proc. Roy. Soc. London Ser. A 361 (1978), 1-20) using a Poisson-Dirichlet "paintbox" and as a consequence, the partition by ages is seen to be equivalent to the size biased permutation of the Poisson-Dirichlet distribution. This approach unifies and extends many results on ages of alleles, the Polya urn, and the Poisson-Dirichlet distribution. Furthermore the Ewens sampling formula is characterized as being the only partition structure which may be generated by an urn-like mechanism.

Age Factors↗
PubMed1985

Dual processes and an invariance result for exchangeable models in population genetics.

By means of a representation as interactive particle systems, dual processes are constructed for a large class of exchangeable models in population genetics. It is shown that as the population size becomes large these dual processes tend in distribution to a particularly tractable limiting dual process. Properties of the models are analyzed using the duality relationship and approximate expressions are obtained for various quantities. Diffusion approximations follow easily from the invariance result.

Animals↗
PubMed1984

Measurement of serum C reactive protein concentration after bone marrow transplantation for leukaemia.

C reactive protein concentration was measured serially in 19 patients with leukaemia after bone marrow transplantation. Six episodes of graft versus host disease occurred in the presence of fever but with no evidence of infection, and these were associated with C reactive protein concentrations as high as 200 mg/l. C reactive protein values were also increased in 12 febrile episodes associated with infection, in seven of which graft versus host disease was also present. C reactive protein concentrations are of no value in differentiating infection from graft versus host disease, but in both cases they may be useful as an objective index of response to appropriate treatment.

Adult↗