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P Donnelly

Publications and source records attributed to P Donnelly.

At least 19 recordsLinked to original sources
PubMed2006

The distribution and causes of meiotic recombination in the human genome.

Using the statistical analysis of genetic variation, we have developed a high-resolution genetic map of recombination hotspots and recombination rate variation across the human genome. This map, which has a resolution several orders of magnitude greater than previous studies, identifies over 25,000 recombination hotspots and gives new insights into the distribution and determination of recombination. Wavelet-based analysis demonstrates scale-specific influences of base composition, coding context and DNA repeats on recombination rates, though, in contrast with other species, no association with DNase I hypersensitivity. We have also identified specific DNA motifs that are strongly associated with recombination hotspots and whose activity is influenced by local context. Comparative analysis of recombination rates in humans and chimpanzees demonstrates very high rates of evolution of the fine-scale structure of the recombination landscape. In the light of these observations, we suggest possible resolutions of the hotspot paradox.

Animals↗
PubMed2005

Public health in practice: the three domains of public health.

This paper outlines a conceptual model for public health practice by proposing the three domains as a framework to organize and to deliver public health programmes. The model builds on the recognition that public health is everybody's business and therefore, needs a common definitional base. Different levels of skill and a wide range of contributions are needed if public health programmes are to make the most impact. The different domains of practice help to construct a basis for understanding the necessary elements of the public health system and their interactions. Using teenage pregnancy as a case study of a public health programme highlights the characteristics of the model. It demonstrates not only the importance of the role of directors of public health in taking a population-based overview, but also the need for multi-sectoral, multidisciplinary working. The relevance of the public health approach not only to primary care but also to the hospital-based sector becomes apparent, as does its relevance to communities, voluntary sector and local government. Integration of the three domains, a common definition and the framework for the public health system will support effective delivery of health improvement.

Models, Organizational↗
PubMed2005

Platelets in the paediatric population: the influence of age and the limitations of automation.

Accurate and precise platelet counting is important for the clinical management of children with platelet disorders. Current automated technologies are often unable to discriminate platelets from non-platelet particles particularly in circumstances where platelet anisocytosis is common. This study compares manual methodology and the automated technologies; impedance, optical density and CD61 immunoplatelet method (available on the Cell Dyn 4000) with the reference method of flow cytometric analysis in a paediatric population. A total of 141 samples were analysed and divided into specific age related groups and groups with thrombocytopenia and thrombocytosis. Data analysis showed that the CD61 method compared best with the reference method and this was evident in all the specified groups. The mean platelet count obtained by optical and manual methods were lower, suggesting that these methods are less reliable. The impedance count method was accurate despite its limitations. Strong correlations were observed in the 2-14 year age group but there was greater variation in the <1 month group supporting the theory that there is a greater variation in platelet characteristics in neonates. The CD61 method is the automated method of choice and would be particularly useful in the problem groups (platelet counts <50 x 10(9)/l and neonates <1 month old).

Adolescent↗
PubMed2003

A reassessment of genetic diversity in Icelanders: strong evidence from multiple loci for relative homogeneity caused by genetic drift.

There has been some controversy in the literature concerning whether Icelanders are genetically homogenous or heterogeneous relative to other European populations. We reassess this question in the light of large data sets spanning 83 autosomal SNP loci, 14 serogenetic loci, 6622 Y-chromosomes and 3214 sequences from mtDNA hypervariable segments 1 and 2 (HVS1 and HVS2). Our results strongly support the hypothesis that genetic drift, with a consequent loss of variation, has had a greater impact on Icelanders than most other Europeans. We also analyse 7245 HVS1 sequences from 25 European populations. In line with other studies, we observe a deficit of rare HVS1 haplotypes and an excess of intermediate frequency haplotypes in Icelanders compared to most European populations, with some measures of genetic diversity indicating relative heterogeneity and others indicating relative homogeneity of Icelanders. Simulations indicate that genetic drift, and not admixture (as proposed by Arnason, 2003) is the most likely cause of the atypical Icelandic HVS1 frequency spectrum. These simulations reveal that gene diversity (heterozygosity) and mean pairwise differences are largely insensitive to events in recent population history, while statistics based on the number of haplotypes or segregating sites are much more sensitive. Overall, our analyses strongly indicate that the Icelandic gene pool is less heterogeneous than those of most other European populations.

Chromosomes, Human, Y↗
PubMed2001

A new statistical method for haplotype reconstruction from population data.

Current routine genotyping methods typically do not provide haplotype information, which is essential for many analyses of fine-scale molecular-genetics data. Haplotypes can be obtained, at considerable cost, experimentally or (partially) through genotyping of additional family members. Alternatively, a statistical method can be used to infer phase and to reconstruct haplotypes. We present a new statistical method, applicable to genotype data at linked loci from a population sample, that improves substantially on current algorithms; often, error rates are reduced by > 50%, relative to its nearest competitor. Furthermore, our algorithm performs well in absolute terms, suggesting that reconstructing haplotypes experimentally or by genotyping additional family members may be an inefficient use of resources.

Algorithms↗
PubMed2001

Case-control studies of association in structured or admixed populations.

Case-control tests for association are an important tool for mapping complex-trait genes. But population structure can invalidate this approach, leading to apparent associations at markers that are unlinked to disease loci. Family-based tests of association can avoid this problem, but such studies are often more expensive and in some cases--particularly for late-onset diseases--are impractical. In this review article we describe a series of approaches published over the past 2 years which use multilocus genotype data to enable valid case-control tests of association, even in the presence of population structure. These tests can be classified into two categories. "Genomic control" methods use the independent marker loci to adjust the distribution of a standard test statistic, while "structured association" methods infer the details of population structure en route to testing for association. We discuss the statistical issues involved in the different approaches and present results from simulations comparing the relative performance of the methods under a range of models.

Alleles↗
PubMed2001

Oral antifungals as prophylaxis in haematological malignancy.

In the standard treatment of patients with haematological malignancy, immunosuppressive therapy produces prolonged periods of neutropenia and mucositis, which increase the risk of systemic fungal infection. In allogeneic bone marrow transplantation, this risk extends well beyond the period of neutropenia when graft-versus-host disease, and its treatment, result in prolonged lymphocytopenia. Various agents are used for antifungal prophylaxis and treatment but all have limitations: amphotericin B is restricted by the need for intravenous infusion and the occurrence of adverse events, fluconazole by its narrow spectrum of activity and the emergence of fluconazole-resistant fungi and itraconazole capsules by erratic absorption. Oral administration of antifungals has clear advantages in prophylaxis and an important current strategy is to maximize the extent and reliability of the oral bioavailability of antifungal agents. Mucositis is the main obstacle for success of strategies based on oral delivery. In this review, the ability of these new oral formulations to deliver sufficient antifungal prophylaxis is evaluated.

Administration, Oral↗
PubMed2001

Likelihoods and simulation methods for a class of nonneutral population genetics models.

Methods for simulating samples and sample statistics, under mutation-selection-drift equilibrium for a class of nonneutral population genetics models, and for evaluating the likelihood surface, in selection and mutation parameters, are developed and applied for observed data. The methods apply to large populations in settings in which selection is weak, in the sense that selection intensities, like mutation rates, are of the order of the inverse of the population size. General diploid selection is allowed, but the approach is currently restricted to models, such as the infinite alleles model and certain K-models, in which the type of a mutant allele does not depend on the type of its progenitor allele. The simulation methods have considerable advantages over available alternatives. No other methods currently seem practicable for approximating likelihood surfaces.

Alleles↗
PubMed2001

Estimating recombination rates from population genetic data.

We introduce a new method for estimating recombination rates from population genetic data. The method uses a computationally intensive statistical procedure (importance sampling) to calculate the likelihood under a coalescent-based model. Detailed comparisons of the new algorithm with two existing methods (the importance sampling method of Griffiths and Marjoram and the MCMC method of Kuhner and colleagues) show it to be substantially more efficient. (The improvement over the existing importance sampling scheme is typically by four orders of magnitude.) The existing approaches not infrequently led to misleading results on the problems we investigated. We also performed a simulation study to look at the properties of the maximum-likelihood estimator of the recombination rate and its robustness to misspecification of the demographic model.

Genetics, Population↗
PubMed2001

Dorothea Dix. An inspirational crusader for political reform and provision of mental health care services.

Traditionally nursing history, that is nurses' collective memory, unique skills and collective experiences, was passed down in a fragmented way throughout training and career. Now nurses are beginning to recognise how vital the study of nursing history is, not only as a tool of unification, but also as a source of pride. Nurses as individuals need to expand their breadth of nursing history knowledge in order to achieve a conscious identity for nursing in the future, not least politically where the future absolutely depends on a sense of collective achievement in the past. The life and works of Dorothea Linde Dix provide a foundation in the political history of nursing and an inspiration for its future.

Health Care Reform↗
PubMed2000

A comparison of manikin CPR performance by lay persons trained in three variations of basic life support guidelines.

This paper reports on a randomised controlled trial comparing the acquisition and retention of cardiopulmonary resuscitation (CPR) skills by lay persons trained in three variations of basic life support. Training was provided either in 1992 European Resuscitation Council (ERC) guidelines, or in the 1997 International Liaison Committee on Resuscitation (ILCOR) Advisory Statement (adopted with minor revisions as 1998 ERC guidelines), and an American Heart Association 'call first' version of the 1997 ILCOR statement. Evaluation of manikin CPR using the established Cardiff tests (CARE and VIDRAP) showed that 51% of those trained in the current ILCOR guidelines performed effectively compared with 38% trained in the ERC 1992 guidelines and 25% trained in the 'call first' variation (P<0.01). Whilst the current ERC and ILCOR guidelines appeared easiest to learn, retention at 6 months was poor (14% effective) irrespective of method.

Adult↗
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↗
PubMed2000

The mutation rate in the human mtDNA control region.

The mutation rate of the mitochondrial control region has been widely used to calibrate human population history. However, estimates of the mutation rate in this region have spanned two orders of magnitude. To readdress this rate, we sequenced the mtDNA control region in 272 individuals, who were related by a total of 705 mtDNA transmission events, from 26 large Icelandic pedigrees. Three base substitutions were observed, and the mutation rate across the two hypervariable regions was estimated to be 3/705 =.0043 per generation (95% confidence interval [CI].00088-.013), or.32/site/1 million years (95% CI.065-.97). This study is substantially larger than others published, which have directly assessed mtDNA mutation rates on the basis of pedigrees, and the estimated mutation rate is intermediate among those derived from pedigree-based studies. Our estimated rate remains higher than those based on phylogenetic comparisons. We discuss possible reasons for-and consequences of-this discrepancy. The present study also provides information on rates of insertion/deletion mutations, rates of heteroplasmy, and the reliability of maternal links in the Icelandic genealogy database.

Base Sequence↗
PubMed2000

Randomised controlled trials of staged teaching for basic life support. 1. Skill acquisition at bronze stage.

We have investigated a method of teaching community CPR in three stages instead of in a single session. These have been designated bronze, silver, and gold stages. The first involves only opening of the airway and chest compression with back blows for choking, the second adds ventilation in a ratio of compressions to breaths of 50:5, and the third is a conversion to conventional CPR. In a controlled randomised trial of 495 trainees we compared the performance in tests immediately after instruction of those who had received a conventional course and those who had had the simpler bronze level tuition. The tests were based on video recordings of simulated resuscitation scenarios and the readouts from recording manikins. Differences occurred as a direct consequence of ventilation being required in one group and not the other, some variation probably followed from unforeseen minor changes in the way that instruction was given, whilst others may have followed from the greater simplicity in the new method of training. A careful approach was followed by slightly more trainees in the conventional group whilst appreciably more in the bronze group remembered to shout for help (44% vs. 71%). A clear advantage was also seen for bronze level training in terms of those who opened the airway as taught (35% vs. 56%), for checking breathing (66% vs. 88%), and for mentioning the need to phone for an ambulance (21% vs. 32%). Little difference was observed in correct or acceptable hand position between the conventional group who were given detailed guidance and the bronze group who were instructed only to push on the centre of the chest. The biggest differences related to the number of compressions given. The mean delay to first compression was 63 s and 34 s, and the mean duration of pauses between compressions was 16 s and 9 s, respectively. Average performed rates were similar in the two groups, but more in the conventional group compressed too slowly whereas more in the bronze group compressed too rapidly. Observations were made for only three cycles of compression, but extrapolating these to the 8 min often considered a watershed for chances of survival for victims of cardiac arrest, an average of 308 compressions would be expected from those using conventional CPR compared with 675 for those using bronze level CPR. The implications of this difference are discussed.

Adult↗
PubMed2000

Testicular dysfunction in men with primary hypothyroidism; reversal of hypogonadotrophic hypogonadism with replacement thyroxine.

OBJECTIVE: Primary hypothyroidism can cause disturbances in normal gonadal function. The aim of this study was to investigate the relationship in men between hypogonadism and primary hypothyroidism and the extent to which free and total testosterone levels rose after introduction of replacement thyroxine. DESIGN: Paired study of patients in a hypothyroid and thyroxine treated state. PATIENTS: Ten men with primary hypothyroidism. MEASUREMENTS: Free and total testosterone, gonadotrophin and prolactin levels before and after thyroxine replacement therapy. RESULTS: Low free testosterone levels (161 +/- 62 pmol/l) demonstrated at the time the men were hypothyroid rose significantly with the commencement of thyroxine replacement (315 +/- 141 pmol/l; P < 0.001). Gonadotrophin levels were not elevated consistent with hypogonadotrophic hypogonadism. Hyperprolactinaemia, which can occur in primary hypothyroidism and cause hypogonadotrophic hypogonadism, was not present in the majority of these patients. However a reduction in prolactin level was evident with thyroxine replacement and a rise in free testosterone levels. CONCLUSION: This suggests an effect of hypothyroidism on gonadotrophin secretion at the level of the hypothalamus-pituitary, either directly or through modulation of prolactin secretion. Low free testosterone may also be a contributing factor to some of the symptoms and signs of hypothyroidism in men.

Adult↗
PubMed2000

Percutaneous endoscopic laser discectomy.

BACKGROUND: The aim of the present paper was to systematically review the literature on percutaneous endoscopic laser discectomy (PELD) with respect to the safety and efficacy of the procedure. Where possible the procedure was compared with open discectomy. METHODS: Studies on PELD were identified using MEDLINE (1984 to December 1999), EMBASE (1974 to December 1999) and Current Contents (1993 to Week 1, 2000). A number of search terms were used: PELD; PLDD (percutaneous laser disc decompression); and laser and (spine or lumbar) and (disc* or disk*). The Cochrane Library was searched from 1966 to issue 4, 1999, using the search terms 'discectomy' or 'discotomy'. Live human studies of patients with lumbar disc prolapses for whom surgery was appropriate were included. Cadaver studies were also included. A surgeon and reviewer independently assessed the retrieved articles for their inclusion in the review. RESULTS: Only 12 papers were identified that related to PELD. The level of evidence for safety and efficacy was low; there were no controlled, blinded or randomized studies. The highest level of evidence came from time series studies. No quantitative analysis could be undertaken for the present review. CONCLUSIONS: Given the extremely low level of evidence available for this procedure it was recommended that the procedure be regarded as experimental until results are available from a controlled clinical trial, ideally with random allocation to an intervention and control group.

Cadaver↗