Biomedical subjects

M Kimmel

Publications and source records attributed to M Kimmel.

At least 19 recordsLinked to original sources

PubMed2007

Robust association of the APOE epsilon4 allele with premature myocardial infarction especially in patients without hypercholesterolaemia: the Aachen study.

BACKGROUND: Genetic influence on the manifestation of coronary artery disease (CAD) and myocardial infarction (MI) has been shown previously. From many candidate genes the APOE (apolipoprotein E) with the major alleles epsilon2/epsilon3/epsilon4 is in the focus of interest. MATERIALS AND METHODS: In 1817 patients admitted for their first left heart catheterization at a premature age (males < 55 and females < 65) the association of APOE alleles with MI was analysed. Genotyping was done by 5' exonuclease assay (TaqMan). RESULTS APOE was significantly associated with hypercholesterolaemia (epsilon4 72% vs. epsilon3 66% vs. epsilon2 51%; P < 0.0001), and premature MI (epsilon4 57% vs. epsilon3 50% vs. epsilon2 41%; P < 0.0001; hazard ratio 1.41, 95%CI 1.14-1.75). In patients without hypercholesterolaemia, the APOE allele epsilon4 was highly predictive for the presence of premature MI (epsilon4 55% vs. epsilon3 45% vs. epsilon2 28%; P < 0.0001; hazard ratio 1.75, 95%CI 1.19-2.57). CONCLUSION: The APOEepsilon4 allele shows a robust association with premature MI independent of hypercholesterolaemia.

Adult↗

PubMed2006

APOE alleles are not associated with calcific aortic stenosis.

OBJECTIVES: To analyse the association of APOE alleles with aortic stenosis (AS) in a large study population. METHODS: Patients with AS (n = 538) and a control group of the same age without heart disease (n = 536) were recruited. Left heart catheterisation was performed and mean gradient, aortic valve area, presence of stenotic coronary artery disease (CAD) and cardiovascular risk factors (hypercholesterolaemia, hypertension, smoking, diabetes mellitus and family history of CAD) were assessed. The frequency of the APOE major alleles e2, e3 and e4 was assessed by genotyping the polymorphisms APOE334 and APOE472 with a 5' exonuclease assay (TaqMan). RESULTS: Mean gradient across the aortic valve in cases was 50 (SD 20) mm Hg corresponding to a mean aortic valve area of 0.84 (SD 0.34) cm(2). 270 patients with AS had stenotic CAD. Among patients with AS, the prevalence of hypercholesterolaemia (64% v 40%, p < 0.001), smoking (43% v 27%, p < 0.001), diabetes (27% v 17%, p < 0.01), family history of CAD (30% v 21%, p </= 0.05), and male sex (65% v 44%, p < 0.001) was higher in those with than in those without CAD. The frequency of the major alleles was not different between cases and controls (APOE e2: 104 (19.3%) v 94 (17.5%); APOE e3: 319 (59.3%) v 332 (61.9%); APOE e4: 115 (21.3%) v 110 (20.5%); all p > 0.10). CONCLUSION: APOE e4 is not associated with AS, reflecting the different genetic backgrounds of CAD and AS.

Aged↗

PubMed2003

A note on distributions of times to coalescence, under time-dependent population size.

Expressions for marginal distributions of times in the time-varying coalescence process are derived. The proposed method allows also for computation of joint probability distribution for pairs, triples, etc. of coalescence times. The expressions derived are useful for (1) extending several statistics from time constant to time-varying case, (2) increasing efficiency and accuracy of simulations in time-varying evolution, and (3) debugging coalescence simulation software.

Animals↗

PubMed2003

New explicit expressions for relative frequencies of single-nucleotide polymorphisms with application to statistical inference on population growth.

We present new methodology for calculating sampling distributions of single-nucleotide polymorphism (SNP) frequencies in populations with time-varying size. Our approach is based on deriving analytical expressions for frequencies of SNPs. Analytical expressions allow for computations that are faster and more accurate than Monte Carlo simulations. In contrast to other articles showing analytical formulas for frequencies of SNPs, we derive expressions that contain coefficients that do not explode when the genealogy size increases. We also provide analytical formulas to describe the way in which the ascertainment procedure modifies SNP distributions. Using our methods, we study the power to test the hypothesis of exponential population expansion vs. the hypothesis of evolution with constant population size. We also analyze some of the available SNP data and we compare our results of demographic parameters estimation to those obtained in previous studies in population genetics. The analyzed data seem consistent with the hypothesis of past population growth of modern humans. The analysis of the data also shows a very strong sensitivity of estimated demographic parameters to changes of the model of the ascertainment procedure.

Data Interpretation, Statistical↗

PubMed2001

An application of a general branching process in the study of the genetics of aging.

A general branching process model is developed to analyse familial dependence in longevity data. A general formula for the survival function of a randomly chosen sibling of an individual of a specified age is derived. The branching process model takes into account that siblings' ages may be censored. This is applied to a data set consisting of lifelengths of siblings of centenarians. Age distributions used in the branching process model are estimated from US Census data from the relevant period. It is demonstrated that there is a marked difference in the survival function according to the formula assuming no familial effect and the empirical survival function estimated from the data; thus, indicating a strong familial component.

Adolescent↗

PubMed2001

Modeling of long-term screening for lung carcinoma.

BACKGROUND: Results from the Mayo Lung Project (MLP), a randomized clinical trial for the early detection of lung carcinoma, were interpreted as proof that the early detection of lung carcinoma by chest X-ray does not reduce the mortality from this disease. Recent analysis of extended follow-up data from the MLP subjects found that after approximately 20 years there still was no apparent difference in lung carcinoma mortality between a study group and a control group. METHODS: To view this result within context, the authors utilized a previously published simulation model of the MLP, with parametric values that were estimated at the time of the original publication based on the data collected by the MLP. RESULTS: The model produced predictions of the extended follow-up statistics that were found to be consistent with the data published in the prior study. The authors believe this provides long-term validation for the model. Conversely, the same model demonstrated that had the study subjects been screened annually for the extended follow-up period, the difference in mortality would be noticeable, even with the low sensitivity of chest X-ray detection. CONCLUSIONS: The results of current study strongly suggest that long-term screening with chest X-ray results in a reduction in lung carcinoma mortality. The limited extent of this benefit is the result of the low sensitivity of chest X-ray as a screening tool.

Follow-Up Studies↗

PubMed2001

DNA dinucleotide evolution in humans: fitting theory to facts.

We examine length distributions of approximately 6000 human dinucleotide microsatellite loci, representing chromosomes 1-22, from the GDB database. Under the stepwise mutation model, results from theory and simulation are compared with the empirical data. In both constant and expanding population scenarios, a simple single-step model with parameters chosen to account for the observed variance of microsatellite lengths produces results inconsistent with the observed heterozygosity and the dispersion of length skewness. Complicating the model by allowing a variable mutation rate accounts for the homozygosity, and introducing a small probability of a large mutation step accounts for the dispersion in skewnesses. We discuss these results in light of the long-term evolution of microsatellites.

Chromosomes, Human↗

PubMed2000

A power analysis of microsatellite-based statistics for inferring past population growth.

We present results concerning the power to detect past population growth using three microsatellite-based statistics available in the current literature: (1) that based on between-locus variability, (2) that based on the shape of allele size distribution, and (3) that based on the imbalance between variance and heterozygosity at a locus. The analysis is based on the single-step stepwise mutation model. The power of the statistics is evaluated for constant, as well as variable, mutation rates across loci. The latter case is important, since it is a standard procedure to pool data collected at a number of loci, and mutation rates at microsatellite loci are known to be different. Our analysis indicates that the statistic based on the imbalance between allele size variance and heterozygosity at a locus has the highest power for detection of population growth, particularly when mutation rates vary across loci.

Evolution, Molecular↗

PubMed1999

Stochastic models of telomere shortening.

Shortening of chromosome ends, known as telomeres, is one of the supposed mechanisms of cellular aging and death. We provide a probabilistic analysis of the process of loss of telomere ends. The first work concerned with that issue is the paper by Levy et al. [J. Molec. Biol. 225 (1992) 951-960]. Their deterministic model reproduced the observed frequencies of viable cells in the in vitro experiments. Arino et al. [J. Theor. Biol. 177 (1995) 45-57] reformulated the model of Levy et al. (1992) in the terms of branching processes with denumerable type space. In the present paper, the mathematical results of Arino et al. (1995) are extended to the case in which cell death is present, in cells with telomeres above and below the critical threshold of length, generally with differing probabilities. Both exact and asymptotic results are provided, as well as a discussion of biological relevance of the results.

Cell Death↗

PubMed1999

Quantitation of minimal residual disease in acute myelogenous leukemia and myelodysplastic syndromes in complete remission by molecular cytogenetics of progenitor cells.

Detection of karyotypic clonal abnormalities are prognostically useful in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS), but cytogenetic methods are not sensitive enough to detect low numbers of residual leukemic cells in patients who have achieved complete remission (CR). Fluorescence in situ hybridization (FISH) and fluorescence activated cell sorting (FACS) were used to investigate the frequency and presence of minimal residual disease (MRD) in AML and MDS patients (n = 28) with monosomy of chromosomes 7, 17 and 18 and trisomy of chromosomes 6, 8, 9 and 10 in CR. MRD was detected in all patients with monosomy 7 (n = 10) and followed by relapse in eight patients after 4.8 +/- 3.1 months. In contrast, persistent leukemic cells occurred in 11/12 patients with trisomy 8, but only three of them relapsed after 7.7 +/- 4.0 months. Cox regression analysis showed that cytogenetic class and levels of clonal cells at CR were related to time to relapse (P = 0.001). The level of MRD identified patients at high and low risk of relapse. High absolute levels of proliferating residual leukemic cells correlated with monosomy 7 and high risk of relapse.

Acute Disease↗

PubMed1999

Rate and directionality of mutations and effects of allele size constraints at anonymous, gene-associated, and disease-causing trinucleotide loci.

We studied the patterns of within- and between-population variation at 29 trinucleotide loci in a random sample of 200 healthy individuals from four diverse populations: Germans, Nigerians, Chinese, and New Guinea highlanders. The loci were grouped as disease-causing (seven loci with CAG repeats), gene-associated (seven loci with CAG/CCG repeats and eight loci with AAT repeats), or anonymous (seven loci with AAT repeats). We used heterozygosity and variance of allele size (expressed in units of repeat counts) as measures of within-population variability and GST (based on heterozygosity as well as on allele size variance) as the measure of genetic differentiation between populations. Our observations are: (1) locus type is the major significant factor for differences in within-population genetic variability; (2) the disease-causing CAG repeats (in the nondisease range of repeat counts) have the highest within-population variation, followed by the AAT-repeat anonymous loci, the AAT-repeat gene-associated loci, and the CAG/CTG-repeat gene-associated loci; (3) an imbalance index beta, the ratio of the estimates of the product of effective population size and mutation rate based on allele size variance and heterozygosity, is the largest for disease-causing loci, followed by AAT- and CAG/CCG-repeat gene-associated loci and AAT-repeat anonymous loci; (4) mean allele size correlates positively with allele size variance for AAT- and CAG/CCG-repeat gene-associated loci and negatively for anonymous loci; and (5) GST is highest for the disease-causing loci. These observations are explained by specific differences of rates and patterns of mutations in these four groups of trinucleotide loci, taking into consideration the effects of the past demographic history of the modern human population.

Alleles↗

PubMed1998

Application of a time-dependent coalescence process for inferring the history of population size changes from DNA sequence data.

Distribution of pairwise differences of nucleotides from data on a sample of DNA sequences from a given segment of the genome has been used in the past to draw inferences about the past history of population size changes. However, all earlier methods assume a given model of population size changes (such as sudden expansion), parameters of which (e.g., time and amplitude of expansion) are fitted to the observed distributions of nucleotide differences among pairwise comparisons of all DNA sequences in the sample. Our theory indicates that for any time-dependent population size, N(tau) (in which time tau is counted backward from present), a time-dependent coalescence process yields the distribution, p(tau), of the time of coalescence between two DNA sequences randomly drawn from the population. Prediction of p(tau) and N(tau) requires the use of a reverse Laplace transform known to be unstable. Nevertheless, simulated data obtained from three models of monotone population change (stepwise, exponential, and logistic) indicate that the pattern of a past population size change leaves its signature on the pattern of DNA polymorphism. Application of the theory to the published mtDNA sequences indicates that the current mtDNA sequence variation is not inconsistent with a logistic growth of the human population.

Algorithms↗

PubMed1998

Dynamic balance of segregation distortion and selection maintains normal allele sizes at the myotonic dystrophy locus.

Myotonic dystrophy (DM), an autosomal dominant neurological disorder, is caused by CTG-repeat expansions at the DMPK locus, with affected individuals having > or = 50 repeats of this trinucleotide. Reduced reproductive fitness of affected individuals and decreased viability of congenital DM have been noted. Expanded CTG-repeat alleles are highly unstable, predominantly yielding even higher repeat sizes. Preferential transmission of longer alleles from heterozygous mothers within the normal size range of alleles also is observed. In view of these observations, it is worth examining how DM has been maintained in human populations for hundreds of generations. We present an analysis of the dynamic properties of a model of joint effects of segregation distortion and selection (intensity of which increases with allele sizes of an individual's genotype). Our mathematical formulation and numerical analyses demonstrate that a weak segregation distortion during female meiosis, together with selection of comparable intensity (within the normal allele size range), can maintain an equilibrium distribution of allele frequencies. Genetic drift, acting in conjunction with the occasional contraction of alleles by mutation, can contribute to the balance of segregation distortion and mutation, in the sense that even weaker selection can explain the observed allele frequencies. The model is applied to CTG-repeat size distributions at the DMPK locus, observed in normal individuals from world populations.

Alleles↗

PubMed1998

Signatures of population expansion in microsatellite repeat data.

To examine the signature of population expansion on genetic variability at microsatellite loci, we consider a population that evolves according to the time-continuous Moran model, with growing population size and mutations that follow a general asymmetric stepwise mutation model. We present calculations of expected allele-size variance and homozygosity at a locus in such a model for several variants of growth, including stepwise, exponential, and logistic growth. These calculations in particular prove that population bottleneck followed by growth in size causes an imbalance between allele size variance and heterozygosity, characterized by the variance being transiently higher than expected under equilibrium conditions. This effect is, in a sense, analogous to that demonstrated before for the infinite allele model, where the number of alleles transiently increases after a stepwise growth of population. We analyze a set of data on tetranucleotide repeats that reveals the imbalance expected under the assumption of bottleneck followed by population growth in two out of three major racial groups. The imbalance is strongest in Asians, intermediate in Europeans, and absent in Africans. This finding is consistent with previous findings by others concerning the population expansion of modern humans, with the bottleneck event being most ancient in Africans, most recent in Asians, and intermediate in Europeans. Nevertheless, the imbalance index alone cannot reliably estimate the time of initiation of population expansion.

Genetics, Population↗

PubMed1997

Computer simulation of expansions of DNA triplet repeats in the fragile X syndrome and Huntington's disease.

The expansion of DNA triplet repeats has been shown to be responsible for about a dozen hereditary diseases. In this paper we are concerned with a computer model of such expansion, applied to the fragile X syndrome and Huntington's disease, for which enough quantitative data have been collected. The nucleotide sequence associated with the fragile X consists of CGG repeats and is located inside the FMR1 gene. In normal individuals there is a variable number of triplet repeats less than 60; in asymptomatic carriers the number of repeats is 60-200 (premutation). From the premutation range, the number of triplet repeats can increase within one generation to more than 200 producing affected individuals. In Huntington's disease the CAG repeats are located inside the HD gene. In normal individuals the number of repeats varies from around 11, up to 34. In the intermediate range (34-37 repeats), the mutability is increased, frequently leading to alleles of more than 37 repeats, and the disease phenotype. The rapid increase of the number of triplet repeats in affected individuals has been proposed to be due to the formation of folded DNA structures (hairpins) and their repair or misrepair. In order to determine if this proposed mechanism is adequate to account for the rapid increase of repeats and the large number of repeats in affected individuals we developed a mathematical model that includes the known mechanisms of hairpin formation, and strand synthesis and repair. Simulations based on the model using realistic probabilities of hairpin formation produced results that corresponded with the observed range of repeats and transition probabilities from normal to affected individuals. Similar modelling has been published for the Huntington's disease data. However, in this paper we demonstrate that a uniform approach works for fragile X and Huntington's disease, although the detailed assumptions of the model have to be different. These difference provide insight into the mechanisms of expansion in both cases. Among these insights is that an apparent threshold in the number of repeats for rapid expansion, and the preference for expansion over contraction, may be accounted for by relative probabilities of hairpin formation, replication, slippage and repair.

Computer Simulation↗

PubMed1997

Estimating clonal heterogeneity and interexperiment variability with the bifurcating autoregressive model for cell lineage data.

We utilize an extension of the variance-components models for cell lineage data in Huggins and Staudte (R.M. Huggins and R.G. Staudte, Variance components models for dependent cell populations. J. Am. Stat. Assoc. 89:19-29 (1994) to analyze NIH3T3 cells grown in two different media. This modeling approach has the advantage of a simple built-in correlation structure between familial members and allows for estimating experimental effects, rather than treating them as random effects. In addition, this methodology gives robust estimates of model parameters together with standard errors required for statistical inference. The importance of clonal heterogeneity and interexperiment variability in modeling eukaryotic cell cycles was previously pointed out by Kuczek and Axelrod (T. Kuczek and D.E. Axelrod, The importance of clonal heterogeneity and interexperimental variability in modeling the eukaryotic cell cycle. Math. Biosci. 79:87-96 (1986). This analysis confirms significantly positive sister-sister correlation when cells are grown in rich or poor medium and negative mother-daughter correlation when cells are grown in poor medium. However, for cells grown in rich medium, Kuczek and Axelrod's analysis gives negative mother-daughter correlations, whereas this analysis gives significant positive mother-daughter correlations.

3T3 Cells↗

PubMed1997

Relative mutation rates at di-, tri-, and tetranucleotide microsatellite loci.

Using the generalized stepwise mutation model, we propose a method of estimating the relative mutation rates of microsatellite loci, grouped by the repeat motif. Applying ANOVA to the distributions of the allele sizes at microsatellite loci from a set of populations, grouped by repeat motif types, we estimated the effect of population size differences and mutation rate differences among loci. This provides an estimate of motif-type-specific mutation rates up to a multiplicative constant. Applications to four different sets of di-, tri-, and tetranucleotide loci from a number of human populations reveal that, on average, the non-disease-causing microsatellite loci have mutation rates inversely related to their motif sizes. The dinucleotides appear to have mutation rates 1.5-2 times higher than the tetranucleotides, and the non-disease-causing trinucleotides have mutation rates intermediate between the di- and tetranucleotides. In contrast, the disease-causing trinucleotides have mutation rates 3.9-6.9 times larger than the tetranucleotides. Comparison of these estimates with the direct observations of mutation rates at microsatellites indicates that the earlier suggestion of higher mutation rates of tetranucleotides in comparison with the dinucleotides may stem from a nonrandom sampling of tetranucleotide loci in direct mutation assays.

Analysis of Variance↗

PubMed1997

Minimal residual disease in acute myelogenous leukaemia and myelodysplastic syndromes: a follow-up of patients in clinical remission.

The majority of patients with acute myelogenous leukaemia (AML) and myelodysplastic syndromes (MDS) relapse, especially those with unfavourable cytogenetics. This study was designed to investigate the presence and frequency of minimal residual disease (MRD) in patients with AML or MDS (n=35) and numerical abnormalities of chromosomes 6, 7, 8, 9, 10, 17 and 18 in clinical remission by using a combination of fluorescence activated cell sorting (FACS), fluorescence in-situ hybridization (FISH) and labelling with bromodeoxyuridine (BUdR). The technique enables the detection of as few as three leukaemic cells in 10(5) normal cells. MRD was detected in 33/35 patients in complete remission (CR). 16 patients relapsed (8/11 with monosomy 7, 4/17 with trisomy 8, and 4/7 with other cytogenetic abnormalities) after a median of 4.8 months (range 3-13). Levels of MRD (P=0.007) and proliferation index (P=0.011) were significantly higher in patients with monosomy 7 than in patients with trisomy 8 or other cytogenetic abnormalities. The percentage of cells in S-phase, the number of abnormal cells and cytogenetic class were related to time to relapse (P=0.001) with S-phase being the single most important prognostic factor (P=0.0001). We conclude that the combination of FACS/FISH/BUdR, which determines the number, phenotype and proliferation rate of very rare leukaemic cells in patients with AML or MDS in clinical remission, provides information that is useful in the identification of patients with high and low likelihood of relapse.

Acute Disease↗