Biomedical subjects

S W Guo

Publications and source records attributed to S W Guo.

47 records · Page 3Linked to original sources

PubMed1989

Determination of enzyme or binding constants using generalized linear models, with particular reference to Michaelis-Menten models.

The estimation of Michaelis-Menten pharmacokinetic parameters in patients with epilepsy receiving phenytoin continues to be a vexing problem. The various approximate methods suggested in the literature have serious shortcomings, primarily due to the role of the error term in the statistical model. In this report we present an accurate statistical approach using the Generalized Linear Interactive Modeling (GLIM) computer package developed by the Numerical Algorithms Group, Oxford, U.K. There are several advantages to this model: a meaningful error term can be maintained by means of a link function, the model can incorporate within-subject and between-subject variables, and additional potential explanatory variables can be added to the model. The method is applied to predicting serum phenytoin levels of pregnant women monitored at monthly intervals during pregnancy and for two to five months after pregnancy. Michaelis-Menten parameters are estimated for each women and compared.

Adult↗

PubMedDate not supplied

Modeling the maternal-age dependency of reproductive failure and genetic fitness.

The offspring of older parents are at a higher risk of suffering low birth weights and congenital birth defects that result from mutations and chromosomal anomalies. When the defect is paternal in origin, it often can be shown that the primary lesion arose during mitotic proliferation of the spermatogonial germ cell population. By contrast, germline mosaicism is seldom invoked to explain the age dependency of maternally derived aberrations because germline proliferation in the ovary is already completed during fetal development. Age-dependent defects of maternal origin might, however, be explained in part by the progressive loss of oocytes during the mother's reproductive life. A large number of oocytes undergo the initial stages of maturation each month, but typically only one completes maturation and is ovulated while the majority are discarded, probably by an apoptotic mechanism. Here we explore the possibility that the monthly choice of oocytes to undergo maturation is influenced by subtle phenotypic characters of those oocytes that may bear genetic defects such as trisomy 21. We have generated a mathematical model to describe the loss kinetics for such mutant oocytes relative to the overall pool of resting oocytes, and we assess evolutionary strategies that would favor their utilization faster than, at the same rate as, or slower than the normal oocytes. This formulation reveals that the slower-rate scheme would effectively diminish the utilization of mutant oocytes in young mothers but would increase the risk of related birth defects for older mothers. Accordingly, we propose that natural selection should have favored the delayed utilization of defective oocytes in a primitive high-mortality culture, but that this evolutionary strategy would be outmoded for modern society, because it would lead to an increased frequency of birth defects for older mothers.

Chromosome Aberrations↗

PubMedDate not supplied

The genetics of phenylthiocarbamide perception.

The ability to taste the bitter compound phenylthiocarbamide (PTC) and related chemicals is bimodal, and all human populations tested to date contain some people who can and some people who cannot taste PTC. Why this trait has been maintained in the population is uncertain but this polymorphism may influence food selection, nutritional status or thyroid metabolism. The gene product that gives rise to this phenotype is unknown, and its characterization would provide insight into the mechanism of bitter taste perception. Although this trait is often considered a simple Mendelian trait, i.e. one gene two alleles, a recent linkage study found a major locus on chromosome 5p15 and evidence for an additional locus on chromosome 7. The development of methods to identify these genes will provide a good stepping-stone between single-gene disorders and polygenic traits.

Antimetabolites↗

PubMedDate not supplied

The power of linkage detection by the transmission/disequilibrium tests.

Despite growing interest in the use of transmission/disequilibrium test (TDT)-type analysis in association studies, there has been surprisingly scant attention paid to the issues as to what factors affect the power of the TDT for linkage detection. We demonstrate in this paper that the power is a function of several genetic parameters including the recombination fraction, penetrance, the age of mutant disease allele, marker allele frequency, recurrent mutation rates at marker and/or disease locus, and initial linkage disequilibrium. In general, TDT has greater power to detect linkage for a 'recessive'-type model than for a 'dominant'-type model. Its power also is higher when there is greater differential in marker allele frequency between disease and normal chromosomes. And since the presence of marker mutation and/or recurrent mutation at the disease locus, or the age of disease mutation, or the initial incomplete linkage disequilibrium, all hasten the process to reach linkage equilibrium, all of them can affect the power of TDT to detect linkage. The effect of marker mutation rate or the mutation rate at the disease locus can be minimal if mutation rates are low. The results on the impact of recombination fraction and of age of mutation on the power of TDT in linkage detection seem to be disheartening for gene mappers of complex diseases: for a disease with small genetic influence, a vastly large sample size is needed to detect the linkage, if the marker is not very close to the disease locus. This is particularly true if the disease is 'old'.

Chromosome Mapping↗

PubMedDate not supplied

Gene-environment interactions and the affected-sib-pair designs.

In genetic mapping of complex traits, the affected-sib-pair method (ASP) and the transmission disequilibrium test (TDT) are two methods of choice. The major appeal of both ASP and TDT is that they do not require the knowledge of mode of inheritance underlying the trait in question. The relative ease and economy for data collection also is the reason for their popularity. The basic idea of the ASP is to identify genes or chromosomal regions through identifying genetic similarity based on phenotypical similarity. TDT, on the other hand, detects susceptibility genes through detecting unusual transmission patterns in families. Since phenotypic similarity can also be caused by environmental similarity, we investigate how the presence of gene-environment interaction (GEI) affects the power of both methods. For a simple one-locus-one-risk-factor model, our results indicate that, in the presence of GEI, methods developed based on marginal penetrance functions (i.e. ignoring the risk factor) can give spurious results. The triangular restriction on allele-sharing probability may no longer be valid. If the environment effect is strong, using exposure-discordant affected sib pairs may have advantage over other designs. Above all, a genetic model involving both genetic and environmental factors behaves differently from a single-locus genetic model.

Analysis of Variance↗

PubMedDate not supplied

Gene-environment interaction and the mapping of complex traits: some statistical models and their implications.

The manifestation of many complex diseases or traits is very likely the result of an inextricable interplay of the biological and the environmental. Yet the role of environmental effect has traditionally been played down, for various reasons. In this paper, some simple statistical models that incorporate gene-environment interaction (GEI) have been proposed and their behavior and implications investigated. These implications concern the conditional independence assumption in likelihood calculation of pedigree data, the fine-tuning of the sib pair method for mapping quantitative traits, apportioning of disease or trait variation due to specific causes. In addition, they concern properties of gene mapping methods that do not take GEI into account, and they bring into question the utility of commonly used measures of genetic effects such as recurrence risk ratio for relative pairs, twin concordance rates, and heritability coefficients. In the presence of GEI, all these measures are functions not only of genetic effects and gene frequency, but also of environmental effects, the distribution of environmental factors in the population, and of GEI. Above all, these measures are all measures of familial aggregation, since they can be significant even in the absence of any genetic component of the disease. Thus their use as indicators of the genetic basis of complex diseases is cast into doubt.

Chromosome Mapping↗

PubMedDate not supplied

Scanning chromosome 17 for psoriasis susceptibility: lack of evidence for a distal 17q locus.

Evidence for a genetically heterogeneous psoriasis susceptibility locus on distal human chromosome 17q has recently been reported [Science 1994;264:1141]. Making use of an independently ascertained collection of 24 multiplex psoriasis kindreds, we have performed a genotyping scan of chromosome 17 using 12 microsatellite markers and analyzed the data using parametric (lod score) as well as novel nonparametric methods. Pairwise lod scores revealed no evidence for linkage to the previously implicated marker D17S784 under any of eight models varying in mode of inheritance, penetrance, and sporadic cases. Homogeneous linkage to D17S784 could be excluded under all four autosomal dominant models tested (Z < - 5.8 at theta = 0.05), and there was no evidence for genetic heterogeneity. All other chromosome 17 markers tested also failed to detect evidence for linkage in any of the kindreds under either a dominant or a recessive model. Although further analysis using affected sib pair methods provided no statistically significant evidence for linkage to any chromosome 17 marker, a cluster of three distal 17q loci displayed a trend towards greater than expected allele-sharing values (observed/expected = 1.10-1.14). These results do not formally confirm the existence of a psoriasis susceptibility locus on the distal long arm of human chromosome 17, but are suggestive of its possible involvement under a polygenic model, warranting its further investigation in familial psoriasis.

Adult↗

PubMedDate not supplied

Variation in genetic identity among relatives.

Genetic identity, or genetic relatedness, among relatives, is a key concept in kin recognition, which in turn is important in models for inclusive fitness and inbreeding avoidance. A mathematical definition is presented for the genetic identity based on the proportion of genome shared identical by descent by two relatives. The method of Guo [Am J Hum Genet 1995;56:1468-1476] is used to compute the variance of the genetic identity for various types of relationships. The method is versatile and can handle any kind of relationship. To illustrate the method, the standard errors of the genetic identity using published human genetic maps are computed.

Analysis of Variance↗

PubMedDate not supplied

Genes preserved in relatives.

The genes of an individual are said to be preserved in his relatives if they possess, collectively, all copies of his genes. We present a method for computing the probability that an individual's genes are preserved in his relatives. Using this method, we compute gene preservation probabilities (up to three linked loci) for a variety of relationships for humans and for haplodiploid species. The results suggest that some widely held notions in ethology and sociobiology seem to be questionable. From the gene preservation viewpoint, two brothers are far from enough to justify the sacrifice of one's own life, because the probability that an individual's genes are preserved in his two siblings is dismally small. The precise probability that an individual's genes are all preserved in a group of his relatives depends on the precise specification of the pedigree structure. We also demonstrate that, for a hymenopteran female, there is no practical difference, in terms of gene preservation probability, between helping her sisters to breed and breeding her own offspring. In fact, since the genes of her sister will be either lost or preserved in her nieces/nephews, it is more appropriate to compare the probability of preserving her genes through her own offspring with that through her nieces/nephews. We show that her chance of preserving all her genes is much higher if she chooses to breed her own offspring instead of helping her sister.

Animals↗

PubMedDate not supplied

Linkage disequilibrium measures for fine-scale mapping: a comparison.

We investigate properties of simple linkage disequilibrium mapping for five measures in the presence of mutation at the marker and/or the disease locus and of initial incomplete linkage disequilibrium. In contrast to the stimulation approach that Devlin and Risch used, we calculate the expected values of various linkage disequilibrium measures under different assumptions based on a framework for linkage disequilibrium mapping. These expected values clearly demonstrate the expected performance of these measures. We find that the impact of marker mutation on their performance depends on the magnitude of the mutation relative to the proximity of the marker (i.e. recombination fraction between the marker and the disease locus). In the presence of recurrent mutation at the marker and/or disease locus, the performance of all measures, including the robust one, depends on the marker allele frequency. The initial incomplete linkage disequilibrium could render all measures useless. These expected values also show clearly why in Devlin and Risch's simulation some measures performed very badly under certain circumstances.

Alleles↗

PubMedDate not supplied

Estimating the age of mutant disease alleles based on linkage disequilibrium.

With more and more disease genes being mapped and/or cloned, there is a growing interest in dating the age of underlying mutations. The knowledge of the age of mutation is important to finely map disease genes by linkage disequilibrium mapping. It would also help us understand the origin, evolution, and dispersion of the mutant disease genes. Despite increasing interests in dating disease mutations, the development of appropriate statistical methods is largely fragmentary, and there is a lack of systematic treatment of the topic. We propose two classes of methods for estimating the age of mutant allele at the disease locus based on linked marker data. Our methods can not handle only single-locus marker data, but also multi-locus marker data as well. Moreover, our methods can be used even when the location of the disease locus is unknown, and/or when there are mutations at the marker or disease locus. We show that some previous results are special cases of our methods. We also derive a recursive equation previously obtained by Serre et al. [Hum Genet 1990;84:449-454] and provide an explicit solution to the equation. To illustrate our methods, we applied them to two groups of data sets, one is cystic fibrosis data collected from several European populations, and the other is data on several genetic diseases (diastrophic dysplasia, progressive myoclonus epilepsy, congenital chloride diarrhea, and Batten disease) all collected from the Finnish population. The former data set allows us to trace the origin and dispersion of the most common mutation for cystic fibrosis. The latter provides an opportunity to examine whether all mutations for these diseases have the same age.

Alleles↗