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PubMed1998

The dynamics of drug action on the within-host population growth of infectious agents: melding pharmacokinetics with pathogen population dynamics.

The use of simple mathematical models to study the kinetics of drug action and decay within vertebrate hosts has a long history with a major objective being to derive drug dosage regimens that optimize efficacy and minimize toxicity to the patient. Mathematical models of the relationship between dosage, route of delivery, drug concentration in defined sites and effect on a particular pathogen are widely used in the pharmacological literature. A more recent literature is that concerned with the population dynamics of pathogen replication within the host subjected to pressures exerted by the human immune system. In this paper we develop a theoretical framework to meld both approaches with the aim of identifying threshold criteria that dictate the optimum pattern of drug administration for pathogen clearance from the host. In particular we show how the percentage reduction in microparasite abundance is related to the pharmacokinetic parameter, AUC, recording the area under the drug concentration-time curve within the treated patient, in terms of the parameters that define the population dynamics of the pathogen and the properties of the drug. Two particular pathogens are examined to illustrate the principles underpinning the dynamics of the pharmacokinetic-population dynamic models, namely HIV and Plasmodium falciparum. Criteria for pathogen persistence or elimination are derived for these specific models based on the definition of a basic reproductive number, R0, which measures the average number of secondary infected target cells in a host generated by a single infected cell (CD4 lymphocyte for HIV, and erythrocyte for P. falciparum) within a population of susceptible cells. For the pathogen to invade the host and persist over time, R0</=1. Under chemotherapeutic regimens, expressions for R0 are derived allowing estimates to be made of the ideal treatment regime required to eliminate the pathogen, both for HIV and P. falciparum malaria.

Animals↗
PubMed2000

Extinction risk of a density-dependent population estimated from a time series of population size.

Environmental threats, such as habitat size reduction or environmental pollution, may not cause immediate extinction of a population but shorten the expected time to extinction. We develop a method to estimate the mean time to extinction for a density-dependent population with environmental fluctuation. We first derive a formula for a stochastic differential equation model (canonical model) of a population with logistic growth with environmental and demographic stochasticities. We then study an approximate maximum likelihood (AML) estimate of three parameters (intrinsic growth rate r, carrying capacity K, and environmental stochasticity sigma(2)(e)) from a time series of population size. The AML estimate of r has a significant bias, but by adopting the Monte Carlo method, we can remove the bias very effectively (bias-corrected estimate). We can also determine the confidence interval of the parameter based on the Monte Carlo method. If the length of the time series is moderately long (with 40-50 data points), parameter estimation with the Monte Carlo sampling bias correction has a relatively small variance. However, if the time series is short (less than or equal to 10 data points), the estimate has a large variance and is not reliable. If we know the intrinsic growth rate r, however, the estimate of K and sigma(2)(e)and the mean extinction time T are reliable even if only a short time series is available. We illustrate the method using data for a freshwater fish, Japanese crucian carp (Carassius auratus subsp.) in Lake Biwa, in which the growth rate and environmental noise of crucian carp are estimated using fishery records.

Animals↗
PubMed2005

Trends in population parameters and best linear unbiased prediction of progeny performance in a European F(2) maize population under modified recurrent full-sib selection.

Recurrent selection is a cyclic breeding procedure designed to improve the mean of a population for the trait(s) under selection. Starting from an F(2) population of European flint maize (Zea mays L.) intermated for three generations, we conducted seven cycles of a modified recurrent full-sib (FS) selection scheme. The objectives of our study were to (1) monitor trends across selection cycles in the estimates of the population mean, additive and dominance variances, (2) compare predicted and realized selection responses, and (3) investigate the usefulness of best linear unbiased prediction (BLUP) of progeny performance under the recurrent FS selection scheme applied. Recurrent FS selection was conducted at three locations using a selection rate of 25% for a selection index, based on grain yield and grain moisture. Recombination was performed according to a pseudo-factorial mating scheme, where the selected FS families were divided into an upper-ranking group of parents mated to the lower-ranking group. Variance components were estimated with restricted maximum likelihood. Average grain yield increased 9.1% per cycle, average grain moisture decreased 1.1% per cycle, and the selection index increased 11.2% per cycle. For the three traits we observed, no significant changes in additive and dominance variances occurred, suggesting future selection response at or near current rates of progress. Predictions of FS family performance in Cn+1 based on mean performance of parental FS families in Cn were of equal or higher precision as those based on the mean additive genetic BLUP of their parents, and corresponding correlations were of moderate size only for grain moisture. The significant increase in grain yield combined with the decrease in grain moisture suggest that the F(2) source population with use of a pseudo-factorial mating scheme is an appealing alternative to other types of source materials and random mating schemes commonly used in recurrent selection.

Breeding↗
PubMed2001

Parentage testing with 14 STR loci and population data for 5 STRs in the Slovenian population.

In order to apply a set of 14 short tandem repeat (STR) loci in parentage testing, we performed a population genetic study on a sample of 260 unrelated people from the Slovenian population. Genotypes for the 14 STRs were determined using three multiplex polymerase chain reactions (PCR) and automated fluorescent detection. The allele frequencies of the STR loci D5S818, D13S317, D7S820, D8S1179 and D18S51 showed no deviation from the Hardy-Weinberg equilibrium and agreed well with other Caucasian populations. We resolved a series of 181 parentage disputes of which 29 were exclusions. In all cases, evidence for exclusion was obtained by at least 4 informative STRs out of the 14 loci analysed. The 14 loci combined comprise a highly discriminating test suitable for paternity and identity testing in the Slovenian population, with an average estimated mutation rate of 1.2x10(-3), a combined calculated power of exclusion of 99.99974% and paternity index (PI) value of >10(6) in 72% of the inclusion cases and >10(5) in 91% of the inclusion cases.

Genetic Carrier Screening↗
PubMed1999

The spectrum of microsatellite loci on chromosomes 7 and 8 in Taiwan aboriginal populations: a comparative population genetic study.

Sixteen microsatellite loci on chromosomes 7 and 8 of Han-Taiwanese and six Taiwan aboriginal populations were systematically analyzed by a high-resolution multiple-fluorescence-based polymerase chain reaction technique. Analysis of allele frequency distribution indicated the genetic divergence among these populations. Several alleles were unique to specific tribes. Only the D8S556 locus deviated from Hardy-Weinberg equilibrium in all tribes. Its F(IS) level, as calculated with the Nei method, was also higher and more homozygous than expected. Therefore, with the exception of D8S556, these variable number of tandem repeats (VNTR) loci are suitable genetic markers for forensic and paternal testing. The F(ST) level, as the proportion of the total variation among these tribes, ranged from 1.4% at the D7S484 locus to 6.8% at the D7S550 locus. The average F(ST) was 3.9%, suggesting that there were substantial variations among these populations. The genetic identity analysis and the genetic distance analysis reached the same conclusions, viz., that the Ami and the Paiwan tribes were genetically close to each other, that the Atayal tribe was relatively unique compared with other tribes, and that the Saisiat tribe was relatively close to the Han-Taiwanese. A dendrogram for these tribes was further constructed by the UPGMA method. These VNTR data not only facilitate forensic and paternity testing, but also provide anthropometric information for further elucidating the relationship of Taiwan populations to the Austronesian family.

Asian People↗
PubMed1990

The effective population size of an age-structured population with a sex-linked locus.

Let a population have the same age distribution and age-specific sex ratios at times 0, 1, 2,..., and let M, F, and L, respectively, be the numbers of males and females in the youngest age group and the generation interval. It can then be shown that if there is a sex-linked locus the fixation probabilities of a neutral allele are respectively 1/3LM or 1/3LF if the allele first appears in one newborn male or in one newborn female. The effective population size can then be derived. It is the same as for a population with discrete generations having the same means, variances, and covariances of male and female progeny during a lifetime and the same number of individuals entering the population per generation.

Age Factors↗
PubMed1982

Population studies of HLA-linked SB antigens and their relative importance in primary MLC typing. Analysis of HLA-D homozygous typing cells and normal heterozygous populations.

SB phenotyping was undertaken on 96 HLA-D homozygous typing cells (HTCs) and 129 normal unselected heterozygous donors in the German population, using Interleukin-2-propagated primed lymphocyte typing (PLT) reagents. The results showed that the SB antigens in the normal population behave as a system of alleles at a single locus in Hardy-Weinberg equilibrium (p approximately equal to 0.20). Estimated gene frequencies in the German population appeared to be significantly different (p less than 0.002) from the North American Caucasian population: the principal differences were increased frequencies of the specificities SB1 and SB4, and decreased frequencies of blanks. Of HLA heterozygous donors 41% typed for two distinct SB specificities; 57% typed for one; and 2% were blank. In the HTC group, 20% typed for two specificities; 68% typed for one; and 12% were blank. Thus, a significant proportion of HLA-D homozygous test cells were, nonetheless, heterozygous for HLA-linked SB antigens. Performance of checkerboard mixed leukocyte cultures (MLCs) between 16 SB typed HLA-Dw3 HTCs, however, did not indicate that the observed mutual or one-way responses were influenced in any simple way by SB antigens; neither heterozygosity nor assumed homozygosity for SB antigens appeared to influence the frequency of MLC typing responses of HLA-Dw3-positive donors on these HTCs. These results add further confirmation of the genetic and functional independence of the SB gene product(s) and the HLA-D/DR gene product(s).

Genes, MHC Class II↗
PubMed2006

Variation of interleukin 8 -251 A>T polymorphism in worldwide populations and intra-ethnic differences in Japanese populations.

BACKGROUND: Interleukin-8 (IL8) is a member of the family of chemokines. The IL8 gene has polymorphic variations, and the genotype of IL8 -251 A>T is associated with smoking behavior and cancer progression. METHOD: IL8 -251 A>T polymorphism were investigated in Japanese, from 5 different areas, in Ovambo, Turkish, Mongolian and Korean populations by PCR with confronting 2-pair primers (PCR-CTPP) analysis. RESULTS: A subpopulation analysis of Japan revealed a north-to-south increase in the frequency of the IL8 -251 T allele. Among the 5 groups, the Japanese showed the highest frequency of mutant allele followed by the Turks. The distribution pattern in the Japanese was different from those of Mongolians and Koreans. In the Ovambo population, no mutant allele homozygote subject was found and the frequency of mutant alleles was the lowest, similar to that in Gambians. CONCLUSION: The present study is the first to demonstrate the Japan population inter-prefecture differences in IL8 -251 A>T polymorphism as well as a certain genetic heterogeneity in the worldwide distribution of IL8 -251 A>T polymorphism. The distribution results may help define the true significance of IL8 -251 A>T polymorphism as a marker for smoking behavior in populations worldwide.

Adenine↗
PubMed2006

Population data from sub-populations of the Northern Territory of Australia for 15 autosomal short tandem repeat (STR) loci.

It is a requirement that forensic DNA profiling evidence be accompanied by an estimation of its weight, in order that the court can assign an appropriate probative value to the evidence during legal proceedings. There are various models by which this estimation can be made, but each relies on approximations of the allele frequencies in the relevant population. It is also important to assess relevant population genetic features of the available data. This report provides allele frequencies and estimates of common population genetic parameters for the major sub-populations of the Northern Territory of Australia genotyped at 15 autosomal short tandem repeat (STR) loci.

Australia↗
PubMed1999

Population-based assessment of the outcome of cataract surgery in an urban population in southern India.

PURPOSE: To assess the outcome of cataract surgery in an urban population in southern India. METHODS: As part of a population-based cross-sectional epidemiologic study, the Andhra Pradesh Eye Disease Study, 2,522 people of all ages, including 1,399 individuals 30 years of age or older, from 24 clusters representative of the population of Hyderabad in southern India underwent a detailed interview and ocular evaluation including logarithm of minimal angle of resolution (logMAR) visual acuity, refraction, slit-lamp biomicroscopy, applanation tonometry, gonioscopy, dilation, cataract grading, aphakia/pseudophakia status, and stereoscopic fundus evaluation. Automated threshold visual fields and slit-lamp and fundus photography were performed when indicated by standardized criteria. Very poor outcome in an eye that had undergone cataract surgery was defined as presenting distance visual acuity worse than 20/200, and poor outcome was defined as visual acuity worse than 20/60 to 20/200. RESULTS: In subjects 50 years of age or older, after adjustment for age and sex distribution, the rate of having had cataract surgery in one or both eyes was 14.6% (95% confidence interval [CI], 11.4% to 17.8%). Of 131 eyes (91 subjects) that had undergone cataract surgery, 28 (21.4%; 95% CI, 14.4% to 28.4%) had very poor outcome and another 40 (30.5%; 95% CI, 22.6% to 38.4%) had poor outcome. The very poor outcome in 20 (71.4%) of 28 eyes and poor outcome in 23 (57.5%) of 40 eyes could be attributed to surgery-related causes or inadequate refractive correction. With multivariate analysis, very poor outcome as a result of surgery-related causes or inadequate refractive correction was more likely to be associated with intracapsular cataract extraction than with extracapsular cataract extraction (odds ratio, 9.34; 95% CI, 2.49 to 35.06) in subjects belonging to the lowest socioeconomic status (odds ratio, 4.92; 95% CI, 1.16 to 20.93) and with date of surgery 3 or fewer years before the survey than with more than 3 years (odds ratio, 4.52; 95% CI, 1.33 to 15.39). Also, very poor or poor outcome as a result of surgery-related causes or inadequate refractive correction was associated with women (odds ratio, 2.55; 95% CI, 1.06 to 6.16). CONCLUSIONS: The very high rate of very poor and poor visual outcome, predominantly as a result of surgery-related causes and inadequate refractive correction, in this urban population of India suggests that more attention is needed to improve the visual outcome of cataract surgery. In order to deal with cataract-related visual impairment in India, as much emphasis on surgical quality, refractive correction, and follow-up care is necessary as on the number of surgeries.

Adult↗
PubMed2000

Is the brown shrimp Crangon crangon (L.) population of the Vaccarès lagoon (Camargue, France, Rhône delta) an annual population?

To study the population dynamics of Crangon crangon in the Vaccarès lagoon in the Camargue (Rhône delta), the age of brown shrimp was determined using the method of Tiews (1954). This method consists in counting the number of segments of the outer branch of the first antenna. This number is correlated with the number of moults already accomplished by the shrimp. The duration of the intermoult depends on water temperature. Adapting this model to our environmental data, we determined the age of the brown shrimp. Hatching of larvae occurs in the sea in May, and juveniles enter the lagoon from June to September. Our results showed that Crangon crangon in the Vaccarès lagoon reached sexual maturity between 6 and 11 months, and individuals are 1 year old when they leave the lagoon. A few adults from the previous year (1+) migrate back to the lagoon the following year, but these older individuals represent only a very small part of the population, and have only been observed occasionally. The Vaccarès brown shrimp population can therefore be considered as annual, in contrast to northern European populations.

Animals↗
PubMed1998

A use of Monte Carlo integration for population pharmacokinetics with multivariate population distribution.

This paper describes a use of Monte Carlo integration for population pharmacokinetics with multivariate population distribution. In the proposed approach, a multivariate lognormal distribution is assumed for a population distribution of pharmacokinetic (PK) parameters. The maximum likelihood method is employed to estimate the population means, variances, and correlation coefficients of the multivariate lognormal distribution. Instead of a first-order Taylor series approximation to a nonlinear PK model, the proposed approach employs a Monte Carlo integration for the multiple integral in maximizing the log likelihood function. Observations below the lower limit of detection, which are usually included in Phase 1 PK data, are also incorporated into the analysis. Applications are given to a simulated data set and an actual Phase 1 trial to show how the proposed approach works in practice.

Algorithms↗
PubMed2002

Population genetic relationships between Mediterranean populations determined by HLA allele distribution and a historic perspective.

HLA genes allele distribution has been studied in Mediterranean and sub-Saharan populations. Their relatedness has been tested by genetic distances, neighbour-joining dendrograms and correspondence analyses. The population genetic relationships have been compared with the history of the classical populations living in the area. A revision of the historic postulates would have to be undertaken, particularly in the cases when genetics and history are overtly discordant. HLA genomics shows that: 1) Greeks share an important part of their genetic pool with sub-Saharan Africans (Ethiopians and west Africans) also supported by Chr 7 Markers. The gene flow from Black Africa to Greece may have occurred in Pharaonic times or when Saharan people emigrated after the present hyperarid conditions were established (5000 years B.C.). 2) Turks (Anatolians) do not significantly differ from other Mediterraneans, indicating that while the Asians Turks carried out an invasion with cultural significance (language), it is not genetically detectable. 3) Kurds and Armenians are genetically very close to Turks and other Middle East populations. 4) There is no HLA genetic trace of the so called Aryan invasion, which has only been defined on doubtful linguistic bases. 5) Iberians, including Basques, are related to north-African Berbers. 6) Present-day Algerian and Moroccan urban and country people show an indistinguishable Berber HLA profile.

Africa South of the Sahara↗
PubMed1975

Population structure, gene flow and natural selection in populations of Euphydryas phaeton.

An examination of seven proteins, presumably encoded by seven structural gene loci, in three local populations of the supposedly sedentary and colonial butterfly, Euphydryas phaeton revealed that three (43 per cent) were polymorphic with three to five alleles each. In addition to this high level of heterozygosity, no statistically significant differences in allele frequencies were found at two of the three polymorphic loci. Since the effective breeding size in each population was estimated to range from as few as 20 to 200 individuals, it appears that some level of gene flow between populations must be invoked to explain the high levels of genetic variability maintained in local populations of this butterfly, despite its apparently colonial nature.

Alleles↗
PubMed2000

Linkage disequilibrium in isolated populations: Finland and a young sub-population of Kuusamo.

Linkage disequilibrium (LD), non-random association of alleles at closely linked chromosomal loci, has been used as a tool in the identification of disease alleles, and this has led to an improved understanding of pathology in many monogenic Mendelian human diseases. We are currently moving from the mapping and identification of monogenic disease loci to attempts at identifying loci involved in predisposition to multifactorial diseases. In the selection of ascertainment strategies in the studies of these complex diseases, the extent of background LD in different populations is an important consideration. Here, we compare the extent of LD among the alleles of linked loci in a randomly ascertained sample of individuals from the Finnish population and a set of individuals ascertained from the region of Kuusamo, a small sub-population, founded some 13 generations ago, which has experienced very little subsequent immigration. Thirty-three microsatellite loci were genotyped in chromosomal regions on 13q, 19q, 21q, Xq, and Xp. The genetic diversity of these loci was determined separately in the general Finnish sample and in the Kuusamo sample. The X-chromosomal loci are characterised by higher levels of LD in the samples from Kuusamo than in the much larger (and older) general population of Finland, whereas in alleles of autosomal loci very little LD was seen in either of these two samples.

Alleles↗
PubMed2006

Hidden population substructures in an apparently homogeneous population bias association studies.

Linkage- and association-based approaches have been applied to attempt to unravel the genetic predisposition for complex diseases. However, studies often report contradictory results even when similar population backgrounds are investigated. Unrecognized population substructures could possibly explain these inconsistencies. In an apparently homogeneous German sample of 612 patients with type 2 diabetic and end-stage diabetic nephropathy and 214 healthy controls, we tested for hidden population substructures and their possible effects on association. Using a genetic vector space analysis of genotypes of 20 microsatellite markers, we identified four distinct subsets of cases and controls. The significance of these substructures was demonstrated by subsequent association analyses, using three genetic markers (UCSNP-43,-19,-63; intron 3 of the calpain-10 gene). In the undivided sample, we found no association between individual SNPs or any haplogenotypes (ie the genotype combination of two multilocus haplotypes) and type 2 diabetes. In contrast, when analyzing the four groups separately, we found that there was evidence for association of the common C allele of UCSNP-63 with the trait in the largest group (n=547 cases/101 controls; P=0.002). In this subset haplotype 112 was more frequent in controls than in cases (P=0.006; haplogenotype 112/121: odds ratio (OR)=0.27, 95% confidence intervals (CI)=0.13-0.57), indicating a protective effect against the development of type 2 diabetes. Our study demonstrates that unconsidered population substructures (ethnicity-dependent factors) can severely bias association studies.

Bias↗
PubMed1999

Isolation by distance in a continuous population: reconciliation between spatial autocorrelation analysis and population genetics models.

Analysis of the spatial genetic structure within continuous populations in their natural habitat can reveal acting evolutionary processes. Spatial autocorrelation statistics are often used for this purpose, but their relationships with population genetics models have not been thoroughly established. Moreover, it has been argued that the dependency of these statistics on variation in mutation rates among loci strongly limits their interest for inferential purposes. In the context of an isolation by distance process, we describe relationships between a descriptor of the spatial genetic structure used in empirical studies, Moran's I statistic and population genetics parameters. In particular, we point out that, when Moran's I statistic is used to describe correlation in allele frequencies at the individual level, it provides an estimator of Wright's coefficient of relationship. We also show that the latter parameter, as a descriptor of genetic structure, is not influenced by selfing rate or ploidy level. Under specific finite population models, numerical simulations show that values of Moran's I statistic can be predicted from analytical theory. These simulations are also used to estimate the time taken to approach a structure at equilibrium. Finally, we discuss the conditions under which spatial autocorrelation statistics are little influenced by variation in mutation rates, so that they could be used to estimate gene dispersal parameters.

Genetics, Population↗
PubMed2003

Gene flow and population history in high dispersal marine invertebrates: mitochondrial DNA analysis of Holothuria nobilis (Echinodermata: Holothuroidea) populations from the Indo-Pacific.

The sea cucumber, Holothuria nobilis, has a long-lived planktotrophic larvae, and previous allozyme surveys have suggested that high dispersal is realized. In contrast, recent ecological studies indicate that dispersal is low. To reconcile these data, and to investigate the evolution of this Indo-Pacific species, we screened geographical variation in 559 bp of a mitochondrial gene (COI) in 360 samples from the Australasian region and La Réunion. Sequences from La Réunion differed by > 7% from others and may constitute another species. Haplotype diversity in other samples was high (0.942, SD = 0.007), but haplotypes were closely related (mean nucleotide diversity: 0.0075, SD = 0.0041). AMOVA, pairwise FST values and exact tests did not detect significant population structure. Nested clade analysis showed that one of two main clades was over-represented in west Australia, whereas the other was more common in the northern Great Barrier Reef. Isolation-by-distance was identified as the main determinant of population structure at several clade levels. Contiguous range expansion was inferred for evolutionary older clade levels and this may correspond to a late Pleistocene (88 000-193 000 years ago) population expansion inferred from haplotype mismatch distributions. Thus, the population genetic structures detected are likely to be formed prior to the last ice age, with some indications for high dispersal on shorter time scales.

Analysis of Variance↗