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PubMedDate not supplied

Analysis of systems influencing renal hemodynamics and sodium excretion. I. Biochemical systems theory.

In this article we present a new methodology--Biochemical Systems Theory and Analysis--as an alternative to traditional parametric statistical procedures for investigating differences between risk groups in a population. We review the systems theory and how it can be used to represent a model of processes influencing renal hemodynamics and sodium (Na+) excretion. We also discuss the potential for new measures of the biology of common diseases that can emerge from a synergism between systems theory and population-based statistical approaches.

Blood Pressure↗
PubMed2001

Linkage disequilibrium mapping: the role of population history, size, and structure.

Linkage disequilibrium mapping attempts to infer the location of a disease gene from observed associations between marker alleles and disease phenotype. This approach can be quite powerful when disease chromosomes are descended from a single founder mutation and the markers considered are tightly linked to the disease locus. The success of linkage disequilibrium map ping in fine-scale localization has led to the suggestion that genome-wide association testing might be useful in the detection of susceptibility genes for complex traits. Such studies would likely be performed in small, relatively isolated founder populations, where heterogeneity of the disease is less likely. To interpret the patterns of association observed in such populations, we need to understand the effect of population size, history, and structure on linkage disequilibrium. In this chapter, we first review measures of allelic association at a single locus. Measures of association between two loci are described, and some theoretical results are reviewed. We then consider some methods for inferring linkage between a marker and a rare disease, focusing on those that model the ancestry of the disease chromosomes. Next we discuss factors whose effect on disequilibrium are understood, and finally we describe the characteristics of some human populations that may be useful for disequilibrium mapping of complex traits.

Analysis of Variance↗
PubMed2000

An inbreeding model of associative overdominance during a population bottleneck.

Associative overdominance, the fitness difference between heterozygotes and homozygotes at a neutral locus, is classically described using two categories of models: linkage disequilibrium in small populations or identity disequilibrium in infinite, partially selfing populations. In both cases, only equilibrium situations have been considered. In the present study, associative overdominance is related to the distribution of individual inbreeding levels (i.e., genomic autozygosity). Our model integrates the effects of physical linkage and variation in inbreeding history among individual pedigrees. Hence, linkage and identity disequilibrium, traditionally presented as alternatives, are summarized within a single framework. This allows studying nonequilibrium situations in which both occur simultaneously. The model is applied to the case of an infinite population undergoing a sustained population bottleneck. The effects of bottleneck size, mating system, marker gene diversity, deleterious genomic mutation parameters, and physical linkage are evaluated. Bottlenecks transiently generate much larger associative overdominance than observed in equilibrium finite populations and represent a plausible explanation of empirical results obtained, for instance, in marine species. Moreover, the main origin of associative overdominance is random variation in individual inbreeding whereas physical linkage has little effect.

Animals↗
PubMed1992

Population growth makes waves in the distribution of pairwise genetic differences.

Episodes of population growth and decline leave characteristic signatures in the distribution of nucleotide (or restriction) site differences between pairs of individuals. These signatures appear in histograms showing the relative frequencies of pairs of individuals who differ by i sites, where i = 0, 1, .... In this distribution an episode of growth generates a wave that travels to the right, traversing 1 unit of the horizontal axis in each 1/2u generations, where u is the mutation rate. The smaller the initial population, the steeper will be the leading face of the wave. The larger the increase in population size, the smaller will be the distribution's vertical intercept. The implications of continued exponential growth are indistinguishable from those of a sudden burst of population growth Bottlenecks in population size also generate waves similar to those produced by a sudden expansion, but with elevated uppertail probabilities. Reductions in population size initially generate L-shaped distributions with high probability of identity, but these converge rapidly to a new equilibrium. In equilibrium populations the theoretical curves are free of waves. However, computer simulations of such populations generate empirical distributions with many peaks and little resemblance to the theory. On the other hand, agreement is better in the transient (nonequilibrium) case, where simulated empirical distributions typically exhibit waves very similar to those predicted by theory. Thus, waves in empirical distributions may be rich in information about the history of population dynamics.

Biological Evolution↗
PubMed2005

Coevolutionary dynamics: from finite to infinite populations.

Traditionally, frequency dependent evolutionary dynamics is described by deterministic replicator dynamics assuming implicitly infinite population sizes. Only recently have stochastic processes been introduced to study evolutionary dynamics in finite populations. However, the relationship between deterministic and stochastic approaches remained unclear. Here we solve this problem by explicitly considering large populations. In particular, we identify different microscopic stochastic processes that lead to the standard or the adjusted replicator dynamics. Moreover, differences on the individual level can lead to qualitatively different dynamics in asymmetric conflicts and, depending on the population size, can even invert the direction of the evolutionary process.

Animals↗
PubMed2004

Pneumococcal meningitis: clinical course and resource use in Western Australian children.

OBJECTIVES: Paediatric pneumococcal meningitis causes high rates of neurological sequelae and is presenting challenges due to the emergence of antibiotic resistance. Diagnosis can be difficult and management is frequently complicated and resource intensive. This population-based study outlines the diagnosis, clinical course and initial resource use of Western Australian (WA) children diagnosed between 1990 and 2000. METHODS: The charts of all rural and metropolitan children discharged from all WA hospitals with International Classification of Disease 9 and 10 codes of pneumococcal or streptococcal meningitis from the Health Department's Hospital Morbidity Data System were reviewed retrospectively. RESULTS: Ninety-four episodes of pneumococcal meningitis were confirmed (median age 12.4 months). Initial diagnosis was often difficult with a suggestive prodrome in less than one quarter of cases and a median of two reviews until diagnosis (range 1-7). The median duration of hospitalization was 11.6 days, 41.5% were admitted to the Intensive Care Unit (ICU), and 47.9% had seizures. There were eight related deaths and neurological sequelae occurred in 24. Initial hospitalization cost on average $A 19,900. Penicillin resistance was first noted in 1993 and occurred in 4.6% of isolates. Most cases (84.5%) were caused by serotypes contained in the currently available seven-valent conjugate vaccine. CONCLUSIONS: Pneumococcal meningitis is often difficult to diagnose, necessitates long and frequently complicated in-patient stays and has high rates of neurological sequelae. It is possible to prevent most cases with new conjugate vaccines.

Adolescent↗
PubMed2006

Approaches to the evaluation of outbreak detection methods.

BACKGROUND: An increasing number of methods are being developed for the early detection of infectious disease outbreaks which could be naturally occurring or as a result of bioterrorism; however, no standardised framework for examining the usefulness of various outbreak detection methods exists. To promote comparability between studies, it is essential that standardised methods are developed for the evaluation of outbreak detection methods. METHODS: This analysis aims to review approaches used to evaluate outbreak detection methods and provide a conceptual framework upon which recommendations for standardised evaluation methods can be based. We reviewed the recently published literature for reports which evaluated methods for the detection of infectious disease outbreaks in public health surveillance data. Evaluation methods identified in the recent literature were categorised according to the presence of common features to provide a conceptual basis within which to understand current approaches to evaluation. RESULTS: There was considerable variation in the approaches used for the evaluation of methods for the detection of outbreaks in public health surveillance data, and appeared to be no single approach of choice. Four main approaches were used to evaluate performance, and these were labelled the Descriptive, Derived, Epidemiological and Simulation approaches. Based on the approaches identified, we propose a basic framework for evaluation and recommend the use of multiple approaches to evaluation to enable a comprehensive and contextualised description of outbreak detection performance. CONCLUSION: The varied nature of performance evaluation demonstrated in this review supports the need for further development of evaluation methods to improve comparability between studies. Our findings indicate that no single approach can fulfil all evaluation requirements. We propose that the cornerstone approaches to evaluation identified provide key contributions to support internal and external validity and comparability of study findings, and suggest these be incorporated into future recommendations for performance assessment.

Benchmarking↗
PubMed2004

Local extinction and recolonization, species effective population size, and modern human origins.

A primary objection from a population genetics perspective to a multiregional model of modern human origins is that the model posits a large census size, whereas genetic data suggest a small effective population size. The relationship between census size and effective size is complex, but arguments based on an island model of migration show that if the effective population size reflects the number of breeding individuals and the effects of population subdivision, then an effective population size of 10,000 is inconsistent with the census size of 500,000 to 1,000,000 that has been suggested by archeological evidence. However, these models have ignored the effects of population extinction and recolonization, which increase the expected variance among demes and reduce the inbreeding effective population size. Using models developed for population extinction and recolonization, we show that a large census size consistent with the multiregional model can be reconciled with an effective population size of 10,000, but genetic variation among demes must be high, reflecting low interdeme migration rates and a colonization process that involves a small number of colonists or kin-structured colonization. Ethnographic and archeological evidence is insufficient to determine whether such demographic conditions existed among Pleistocene human populations, and further work needs to be done. More realistic models that incorporate isolation by distance and heterogeneity in extinction rates and effective deme sizes also need to be developed. However, if true, a process of population extinction and recolonization has interesting implications for human demographic history.

Animals↗
PubMed2001

Effect of race, genetic population structure, and genetic models in two-locus association studies: clustering of functional renin-angiotensin system gene variants in hypertension association studies.

Previous genetic association studies have overlooked the potential for biased results when analyzing different population structures in ethnically diverse populations. The purpose of the present study was to quantify this bias in two-locus association studies conducted on an admixtured urban population. We studied the genetic structure distribution of angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensinogen methionine/threonine (M/T) polymorphisms in 382 subjects from three subgroups in a highly admixtured urban population. Group I included 150 white subjects; group II, 142 mulatto subjects, and group III, 90 black subjects. We conducted sample size simulation studies using these data in different genetic models of gene action and interaction and used genetic distance calculation algorithms to help determine the population structure for the studied loci. Our results showed a statistically different population structure distribution of both ACE I/D (P = 0.02, OR = 1.56, 95% CI = 1.05-2.33 for the D allele, white versus black subgroup) and angiotensinogen M/T polymorphism (P = 0.007, OR = 1.71, 95% CI = 1.14-2.58 for the T allele, white versus black subgroup). Different sample sizes are predicted to be determinant of the power to detect a given genotypic association with a particular phenotype when conducting two-locus association studies in admixtured populations. In addition, the postulated genetic model is also a major determinant of the power to detect any association in a given sample size. The present simulation study helped to demonstrate the complex interrelation among ethnicity, power of the association, and the postulated genetic model of action of a particular allele in the context of clustering studies. This information is essential for the correct planning and interpretation of future association studies conducted on this population.

Alleles↗
PubMed1991

Some indices pertaining to the leprosy control programme in Tamil Nadu, based on data from a random sample of fourteen government control units.

From a random sample of 14 Government Leprosy Control Units in Tamil Nadu, information on the profile of the newly-diagnosed leprosy patients and some important aspects of the control programme in 1978-81 was collected when monotherapy with dapsone was the practice. Among the new patients, 55 per cent were males, 24 per cent were children, 6 per cent had lepromatous leprosy and 9 per cent had a deformity. About 65 per cent were detected by active case-finding methods and 25 per cent were voluntary referrals. Of the total diagnosed patients, only 68 per cent started treatment; further, of these, about 40 per cent collected drugs for at least 6 months in the first year of treatment. The average attendance at the clinic was 34 per cent of the due attendance. Coverage in the annual examination of family contacts was 57 per cent. During the 4 yr period, about 70 per cent of the villages had population surveys with a coverage of 75 per cent or more. The introduction of multi-drug therapy has provided a new impetus to the programme and therefore a similar study is called for to provide valuable information about the extent of improvement in completion rates and overall impact.

Adolescent↗
PubMed2000

Zygotic associations and multilocus statistics in a nonequilibrium diploid population.

The usual approach to characterizing and estimating multilocus associations in a diploid population assumes that the population is in Hardy-Weinberg equilibrium. The purpose of this study is to develop a set of summary statistics that can be used to characterize and estimate the multilocus associations in a nonequilibrium population. The concept of "zygotic associations" is first expanded to facilitate the development. The summary statistics are calculated using the distribution of a random variable, the number of heterozygous loci (K) found in diploid individuals in the population. In particular, the variance of K consists of single-locus and multilocus components with the latter being the sum of zygotic associations between pairs of loci. Simulation results show that the multilocus associations in the variance of K are detectable in a sample of moderate size (> or =30) when the sum of all pairwise zygotic associations is greater than zero and when gene frequency is intermediate. The method presented here is a generalization of the well-known development for the Hardy-Weinberg equilibrium population and thus may be of more general use in elucidating the multilocus organizations in nonequilibrium and equilibrium populations.

Analysis of Variance↗