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PubMed1991

Biochemical genetic differences in vulnerability to drug effects: is statistically significant always physiologically important and vice versa?

The goal of biochemical genetic experiments, which are designed to better understand vulnerability to drug effects, is to determine variation in biochemical traits which can account for variation in behavioral and physiological effects of drugs. Biochemical genetic experiments commonly span several distinct scientific disciplines and many different methodologies, both behavioral and biochemical. In most cases, biochemical genetic experiments involve at least three different levels of analysis, including sophisticated mathematical models of genetic inheritance, many behavioral paradigms used to assess various drug-related phenotypes, and a variety of biochemical methodologies used to determine biochemical correlates. Both the multidisciplinary nature of this scientific endeavor and the traditional uses of the scientific methods which are now being applied to pharmacogenetic experiments necessitate careful consideration of many often conflicting theoretical perspectives in the process of interpretation of experimental results. Several scientific considerations are discussed which emphasize the presentation of the results of pharmacogenetic studies within the context of expectations concerning genetic variance as well as traditional uses and assumptions related to methodology.

Animals↗
PubMed1984

A statistical test for detection of ancestral genetic contributions to disease occurrence in finite populations.

We have been investigating cancer patterns in the Hutterites, a religious isolate residing on communal farms [Martin et al, 1980a,b,c]. Advantages of this population include extensive and accurate genealogies, essentially complete case ascertainment, and relatively uniform environmental background with regard to geographic location, lifestyle, and diet. However, application of the common epidemiological approach to familial risk assessment based on incidence in relatives of index cases [Haenszel, 1959] posed difficulties because all cases are probands. We also planned to employ matching to control for important confounders and thus had to deal with the problems of the matching of cases and controls as well as the existence of complex inbreeding [Hauck and Martin, 1982]. Our basic approach was to compare coefficients of kinship (Fm, a measure of coancestry) of cases with each other to coefficients between cases and matched controls drawn from the same population. We have developed a paired t-type statistic to assess the significance of observed differences. We present, as examples, application of our methods to the analysis of Hutterite data on neurofibromatosis, known to be inherited in autosomal dominant fashion, and on cancer. Neurofibromatosis showed significant familial aggregation, as expected. Breast, colon-rectal, and stomach cancer did not. We then show how to evaluate power and to determine appropriate sample sizes for detecting specified increases in kinship.

Biometry↗
PubMed2000

Geographic patterns: how to identify them and why.

Geographic patterns of genetic diversity allow us to make inferences about population histories and the evolution of inherited disease. The statistical methods describing genetic variation in space, such as estimation of genetic variances, mapping of allele frequencies, and principal components analysis, have opened up the possibility to reconstruct demographic processes whose effects have been tested by a variety of approaches, including spatial autocorrelation, cladistic analyses, and simulations. These studies have significantly contributed to our understanding of human genetic variation; however, the molecular data that have accumulated since the mid-1980s have also created new complications. Reasons include the generally limited sample sizes, but, more generally, it is the nature of molecular variation itself that makes it necessary to develop and apply specific models and methods for the treatment of DNA data. The foreseeable diffusion of laboratory techniques for the rapid typing of many DNA markers will force us to change our approach to the study of human variation anyway, moving from the gene level toward the genome level. Because extensive variation among loci is the rule rather than the exception, an important practical tip is to be skeptical of inferences based on single-locus diversity.

Biological Evolution↗
PubMed2002

Construction of stochastic context trees for genetic texts.

A method has been developed for constructing a tree source model for genetic text generation. Model visualisation in the form of suffix (context) trees provides a new way of context analysis of symbol sequences. Estimation of the stochastic complexity of the data in the frame of the model serves as a criterion for the model's ascertainment. The model and complexity values are used for analysis of genetic texts. The software realisation of this algorithm enables to reveal statistical properties of genetic sequences based on an information measure. The program developed is available via Internet at http://wwwmgs.bionet.nsc.ru/mgs/programs/complexity/.

DNA↗
PubMed1984

Sense and nonsense in genetic epidemiology: a critique of the statistical model of Williams and Iyer.

The statistical model for the analysis of twin-family data of Williams and Iyer is examined. The model uses a large number of redundant parameters. It does not lead to quantitative predictions for new relationships. It allows for epistasis but not dominance. It makes assumptions about assortative mating which are inconsistent with any biologically plausible mechanism. It assumes that the environmental correlation between parent and offspring is due to the direct effect of the parental genotypes, not phenotypes, on offspring environment. Other models which avoid these problems are more appropriate for the analysis of extended twin-family data.

Analysis of Variance↗
PubMed1994

[Computer technology for genetic-geographical study of the gene pool. II. Statistical transformation of maps].

Transformations of computer maps of geographical distribution of gene frequencies using basic mathematical statistical procedures are considered. These transformations are designated as statistical transformation of maps. Two transformation groups are considered: of one map separately and of a group of maps. Transformations possess a value beyond their use as intermediate stages of more complicated cartographical analysis: the resulting maps carry entirely new information on the geography of genes or a gene pool. This article considers three examples of obtaining new genetic profiles using statistical transformation algorithms. These profiles are of: heterozygosity (of HLA-A, B, C loci in northeastern Eurasia); (2) disease risk (Rh-incompatibility of mother and child with simultaneous registration of Rh and ABO blood groups in Eastern Europe); (3) genetic distances (from own mean ethnic values for Belarus' and from mean Russian values for the gene pool of Eastern Europe).

ABO Blood-Group System↗
PubMed2000

Use of closely related affected individuals for the genetic study of complex diseases in founder populations.

We propose a method, the maximum identity length contrast (MILC) statistic, to locate genetic risk factors for complex diseases in founder populations. The MILC approach compares the identity length of parental haplotypes that are transmitted to affected offspring with the identity length of those that are not transmitted to affected offspring. Initially, the statistical properties of the method were assessed using randomly selected affected individuals with unknown relationship. Because both nuclear families with multiple affected sibs and large pedigrees are often available in founder populations, we performed simulations to investigate the properties of the MILC statistic in the presence of closely related affected individuals. The simulation showed that the use of closely related affected individuals greatly enhances the power of the statistic. For a given sample size and type I error, the use of affected sib pairs, instead of affected individuals randomly selected from the population, could increase the power by a factor of two. This increase was related to an increase of kinship-coefficient contrast between haplotype groups when closely related individuals were considered. The MILC approach allows the simultaneous use of affected individuals from a founder population and affected individuals with any kind of relationship, close or remote. We used the MILC approach to analyze the role of HLA in celiac disease and showed that the effect of HLA may be detected with the MILC approach by typing only 11 affected individuals, who were part of a single large Finnish pedigree.

Celiac Disease↗
PubMed2002

Trend tests for case-control studies of genetic markers: power, sample size and robustness.

The Cochran-Armitage trend test is commonly used as a genotype-based test for candidate gene association. Corresponding to each underlying genetic model there is a particular set of scores assigned to the genotypes that maximizes its power. When the variance of the test statistic is known, the formulas for approximate power and associated sample size are readily obtained. In practice, however, the variance of the test statistic needs to be estimated. We present formulas for the required sample size to achieve a prespecified power that account for the need to estimate the variance of the test statistic. When the underlying genetic model is unknown one can incur a substantial loss of power when a test suitable for one mode of inheritance is used where another mode is the true one. Thus, tests having good power properties relative to the optimal tests for each model are useful. These tests are called efficiency robust and we study two of them: the maximin efficiency robust test is a linear combination of the standardized optimal tests that has high efficiency and the MAX test, the maximum of the standardized optimal tests. Simulation results of the robustness of these two tests indicate that the more computationally involved MAX test is preferable.

Case-Control Studies↗
PubMed2007

The elusive goal of pedigree weights.

Non-parametric linkage analysis methods generally involve calculating an allele-sharing statistic for each pedigree in a data set, then standardizing and summing the statistics over pedigrees. Pedigrees of different sizes can be weighted differently in the sum, though it is perhaps most common to weight all standardized pedigree statistics equally. Most other common weighting schemes are based on the number of affected individuals in the pedigree. It is also possible to derive optimal weights, which maximize power to detect linkage under particular trait models. We started by investigating three different analytical and simulation-based methods to calculate power and derive optimal weights. We found that simulation methods produce noticeably more accurate power calculations than the other methods. However, although the different calculation methods give different "optimal" weights, the power at those weights is very similar. That is, the analytical calculation methods are sufficient for finding good weights even though the simulation methods are most appropriate for calculating power. In comparing optimal weights for different trait models, we found that the weights vary quite a bit with the model, such that optimal weights for one model are not necessarily powerful at all for other models. Finally, we studied the power of a number of general weighting schemes, and of some new ones that incorporate information on how closely the affected individuals are related. We were able to find some schemes that performed well in the sense of giving reasonably powerful weights for most of the trait models and pedigree types we considered.

Chromosome Mapping↗
PubMed2003

Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area.

Deciphering the structure of pathogen populations is instrumental for the understanding of the epidemiology and history of infectious diseases and for their control. Although Mycobacterium tuberculosis is the most widespread infectious agent in humans, its actual population structure has remained hypothetical until now because: (i) its structural genes are poorly polymorphic; (ii) adequate samples and appropriate statistics for population genetic analysis have not been considered. To investigate this structure, we analysed the statistical associations (linkage disequilibrium) between 12 independent M. tuberculosis minisatellite-like loci by high-throughput genotyping within a model population of 209 isolates representative of the genetic diversity in an area with a very high incidence of tuberculosis. These loci contain variable number tandem repeats (VNTRs) of genetic elements named mycobacterial interspersed repetitive units (MIRUs). Highly significant linkage disequilibrium was detected among the MIRU-VNTR loci in this model. This linkage disequilibrium was also evident when the MIRU-VNTR types were compared with the IS6110 restriction fragment length polymorphism types. These results support a predominant clonal evolution of M. tuberculosis.

Bacterial Typing Techniques↗
PubMed2005

A note on ENDOG: a computer program for analysing pedigree information.

The aim of this note is to describe the program ENDOG (v.3.0). The program handles pedigree information to conduct several demographic and genetic analyses including: (a) the individual inbreeding and average relatedness coefficients; (b) effective population size; (c) parameters characterizing the concentration of both gene and individuals origin such as the effective number of founders and ancestors, the effective number of founder herds; (d) F statistics and paired genetic distances for each subpopulation under study; (e) descriptors of the genetic importance of the herds in a population and (f) generation intervals. The program will help breeders and researchers to monitor the changes in genetic variability and population structure with limited costs of preparing datasets. The program, user's guide and example file can be down-loaded free of charge from the World Wide Web at http://www.ucm.es/ info/prodanim/Endog30.zip.

Animals↗
PubMed1984

Information gain in joint linkage analysis.

The advent of DNA sequencing and the prospect of the availability of very large numbers of marker loci have reawakened interest in linkage studies. Statistical analyses of linked genetic loci have previously been based on pairwise analysis of the loci, and/or have assumed a known ordering of them along the chromosome. For the sizes of sample available in human medical genetics, pairwise analysis may be a statistically inefficient and inconclusive procedure. It is shown that three-way data provide very much more information, particularly with regard to the problem of ordering the loci. Correct answers to questions of locus order are of particular importance in current approaches to fetal diagnosis, where counselling is based on genotypes at markers closely linked to a disease locus. Although the three-locus analysis of this paper is only a first step towards joint analysis of multilocus data, the qualitative form of the data is of the joint pattern of cosegregation of loci. The pairwise counts of recombinants and nonrecombinants used for pairwise analysis are both qualitatively and quantitatively less informative. Many practical and theoretical problems of multilocus analysis of data remain to be solved, but the practical importance of doing so is demonstrated.

Animals↗
PubMed2003

Testing the "malaria hypothesis" for the case of Thailand: a genetic appraisal.

This study provides statistical analyses of allele frequencies for populations of Thailand, with an attempt to trace the roles of differential malarial selection and genetic admixtures on the observed frequency variation of certain red cell genetic abnormalities (the two beta-globin variants--hemoglobin E and beta-thalassemia--and G-6PD deficiency), probably evolving under malarial endemicity. It is found that frequencies of hemoglobin E vary accordingly with those of G-6PD deficiency, and with diverse malarial ecology. The levels of genetic diversity are greater for hemoglobin E and G-6PD deficiency than for most other nonmalarial related genetic markers, suggesting the evolution of these two genetic abnormalities under differential selection. Results of the Mantel's statistical test for correspondence between distance matrices suggest distinctive patterns of allele frequency differentiation between malarial-related and nonmalarial-related genetic loci. Correlations between beta-globin and G-6PD genetic distances, as well as those between both sets of distances and the malarial distances, are statistically significant. On the other hand, a correlation between malarial distances and the genetic distances for nonmalarial-related genetic loci is not significant statistically. A correlation between the beta-globin genetic distances and the genetic distances for nonmalarial-related genetic loci is, however, statistically significant. The latter result could be attributed largely to the clustering of relatively high hemoglobin E frequencies among genetically closely related populations of northeastern Thailand, whose recent homeland was Laos. The consistently low frequencies of beta-thalassemia observed in most studied populations are explained as a result of the replacement of this genetic variant by hemoglobin E, under long-term malarial selection.

Alleles↗
PubMed1988

A genetic history of Italy.

Statistical techniques for displaying the geographical distribution of many genes in few synthetic images have been used to represent the various patterns of gene frequencies in Europe and in the world (Menozzi et al. 1978; Piazza et al. 1981 a). It has also been shown that such synthetic displays are particularly useful in detecting clines of genetic differentiation associated with movements of populations like those accompanying the Neolithic expansion of farmers from the Near East or, in more recent times, the putative diffusion of Indo-European-speaking populations (Ammerman & Cavalli-Sforza, 1984; Gimbutas, 1973). In this paper we use the same combination of statistical and graphical techniques to study the genetic structure of Italy, a European country whose unity of people and cultures was quite a recent event. The possibility of studying genetic differentiation in a small geographical area is tested and trends of genetic differences are tentatively interpreted in terms of historic and linguistic knowledge. The few demographic pieces of information taken from historical sources and compared with linguistic records support the hypothesis that the genetic structure of Italy still reflects the ethnic stratification of pre-Roman times.

Blood Group Antigens↗
PubMed1995

Influence of social factors on sugary products behavior in 4-year-old children with regard to dental caries experience and information at child health centers.

The aim was to analyze the steering effects of 15 social factors on sugary products behavior at 4 years of age in 177 children. The parents had in most cases received information on dental health care at child health centers, with due respect to the level of caries among the children, who were classified as 'healthy' (no caries experience) (n = 83) or 'diseased' (caries experience) (n = 84). The parents filled in a mailed diet history form. Only sugary products unsuitable from a cariologic point of view were considered. The products were given scores reflecting the frequency of intake. The social factors were social background, family, information, and conceptual factors. By means of multiple regression analysis, explanatory values of the social variables for sugary products behavior were estimated. For the total material, 13% of the variance was explained by all variables combined. Among the social background factors, 'parents' age' was statistically significant (p < 0.05). Among family factors, 'day-care mainly at home' and 'oldest child' were the most important. All information factors proved to be nonsignificant. Of the conceptual factors, only 'importance of genetic factors' was statistically significant. For the healthy group 26% of the variance was explained by all variables. 'Mother's age', 'importance of genetic factors', and 'oldest child' were statistically significant. For the diseased group all variables were nonsignificant. Explanatory values were negligible. The important conclusions were that very few traditionally conceived social variables seem to influence 4-year-old children's sugar behavior. Parents of children with caries appear to be a heterogeneous group with an irrational behavior.

Attitude to Health↗
PubMed1994

Segregation analyses of four urinary caffeine metabolite ratios implicated in the determination of human acetylation phenotypes.

Human acetylation phenotypes were determined with caffeine (137X) as the test substance, improved by measuring urinary caffeine metabolites with a previously described HPLC method. Caffeine, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (IX), 1-methyluric acid (IU), 1,7-dimethylxanthine (17X), and 1,7-dimethyluric acid (17U) were quantified. This study tested the hypothesis, suggested by previous studies, that the acetylation polymorphism is strongly influenced by a major gene. Phenotypes were assessed by using four urinary caffeine metabolite ratios: AFMU/1X, AFMU/[1X + 1U + 17U], AFMU/[AFMU + 1X + 1U], and AFMU/[1X + 1U + 17X + 17U] in a population included 281 nuclear family members who were healthy volunteer subjects. Each urinary ratio revealed strong familial aggregation with correlations between parents and offspring varying from 0.340 to 0.486 as a function of the ratio considered, and between sibs from 0.410 to 0.512 whereas correlations among spouses were not significant, excluding an effect of environmental factors. Segregation analyses were conducted upon these four ratios testing a series of specific models of inheritance and gave evidence for single locus control of N-acetyltransferase (NAT) activity, with Mendelian codominant transmission using the AFMU/1X, AFMU/[1X + 1U + 17U], and AFMU/[1X + 1U + 17X + 17U] ratios. The slow allelic frequencies were 0.739, 0.753, and 0.724, respectively, and the phenotypic concordance was 90 to 92% with the AFMU/1X ratio. The familial aggregation observed in using the AFMU/[AFMU + 1X + 1U] ratio was consistent with a recessive transmission for the allele controlling the homozygous slow phenotype. This last ratio is not convenient to differentiate rapid heterozygous and homozygous phenotype. Considering the number of misclassified subjects, this study would be completed by genotyping the same families as demonstrated by some authors who predicted 97.5% of acetylation phenotype when using PCR-based DNA amplification test.

Acetylation↗