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PubMed2004

Cell cycle progression.

In this paper we consider cell cycle models for which the transition operator for the evolution of birth mass density is a simple, linear dynamical system with a stochastic perturbation. The convolution model for a birth mass distribution is presented. Density functions of birth mass and tail probabilities in n-th generation are calculated by a saddle-point approximation method. With these probabilities, representing the probability of exceeding an acceptable mass value, we have more control over pathological growth. A computer simulation is presented for cell proliferation in the age-dependent cell cycle model. The simulation takes into account the fact that the age-dependent model with a linear growth is a simple linear dynamical system with an additive stochastic perturbation. The simulated data as well as the experimental data (generation times for mouse L) are fitted by the proposed convolution model.

Animals↗

PubMed1999

Cross-sectional and longitudinal relationships among age, cognition, and processing speed.

Cross-sectional and longitudinal age effects on cognitive function were examined in 302 older adults followed longitudinally. Processing speed was related to cognitive performance at cross-section, and change in speed predicted within-person longitudinal cognitive decline. Statistical control of processing speed greatly reduced cross-sectional age effects but did not attenuate longitudinal aging effects. This difference in processing speed's ability to account for cross-sectional and longitudinal age effects is discussed in the context of theories of cognitive aging and methodological and statistical issues pertaining to the cross-sectional and longitudinal study of cognitive aging.

Age Factors↗

PubMed1996

Behavioral capabilities and mortality risk in adults with and without Down syndrome.

Among adults with mental retardation, mortality rates for those with Down syndrome are higher than for those without Down syndrome. We studied age-related changes in functioning and their relation to subsequent mortality in adults with mental retardation. Among people without Down syndrome, recent loss of basic skills was associated with substantially elevated mortality rates. This was not so in the Down syndrome group, however. Adults with Down syndrome tended to experience regression in adaptive behavior earlier than did those without Down syndrome. Incidence rates in the two groups diverged subsequent to age 40. Adults without Down syndrome, however, did also tend to regress when older.

Activities of Daily Living↗

PubMed1994

Evaluation of screening methods for Down's syndrome using bootstrap comparison of ROC curves.

This paper concerns the prediction of fetal Down's syndrome in pregnant women. Down's syndrome is the most common congenital cause of severe mental retardation. We elaborate two predictive functions of trisomy 21, combining maternal age and a maternal serum marker. We evaluated them by means of receiver operating characteristic (ROC) curves which give a representation of sensitivity and specificity of a prediction model when varying the cutoff of the predictor on the whole spectrum. Since normal statistical methods for comparison of ROC curves rely on distributional assumptions which were not verified, we used bootstrapping of ROC curves as a check for the statistical significance of differences between the areas under the curves.

Algorithms↗

PubMed2005

Molecular evolution of the primate developmental genes MSX1 and PAX9.

In primates, the craniofacial skeleton and the dentition are marked by high levels of interspecific variation. Despite this, there are few comparative species studies conducted at the molecular level to investigate this functional diversity. We have determined nucleotide sequences of MSX1 and PAX9, two developmental genes, in a sample of 27 diverse primate species in order to identify coding or regulatory variation that may be associated with phenotypic diversity. Our analyses have identified four highly conserved noncoding sequences, including one that is conserved across primates and with dogs but not with mice. Although we find that substitution rates vary significantly across MSX1 exons, comparisons of nonsynonymous and synonymous substitution rates (dN/dS) suggest that, as a whole, MSX1 and PAX9 amino acid sequences have been under functional constraint throughout primate evolution. Compared to all other primates in our sample, our analysis of exon 1 in MSX1 finds an unusual pattern of amino acid substitution for Tarsius syrichta, a member of a lineage (tarsiers) that has many unique features among primates. For example, tarsiers are the only extant primates without deciduous incisors, and MSX1 is expressed exclusively in the incisor regions during the earliest stages of dental development. Our overall results provide insight into the utility of comparative species analyses of highly conserved developmental genes and their roles in the evolution of complex phenotypes.

Amino Acid Sequence↗

PubMed2005

Semiparametric analysis of survival data with left truncation and dependent right censoring.

Studies of chronic life-threatening diseases often involve both mortality and morbidity. In observational studies, the data may also be subject to administrative left truncation and right censoring. Because mortality and morbidity may be correlated and mortality may censor morbidity, the Lynden-Bell estimator for left-truncated and right-censored data may be biased for estimating the marginal survival function of the non-terminal event. We propose a semiparametric estimator for this survival function based on a joint model for the two time-to-event variables, which utilizes the gamma frailty specification in the region of the observable data. First, we develop a novel estimator for the gamma frailty parameter under left truncation. Using this estimator, we then derive a closed-form estimator for the marginal distribution of the non-terminal event. The large sample properties of the estimators are established via asymptotic theory. The methodology performs well with moderate sample sizes, both in simulations and in an analysis of data from a diabetes registry.

Analysis of Variance↗

PubMed1996

Outcome of neurological decompression illness: development of a manifestation-based model.

A significant proportion neurological decompression illness cases remain symptomatic after the first recompression treatment. Currently, the factors that predict an incomplete resolution are poorly defined. In this study, 214 cases of neurological decompression illness were reviewed and classified according to the presenting manifestations and outcome after a standard therapeutic regimen. The neurological manifestations were classified by type (loss of sensory or motor function, or loss of consciousness) and then by either the number of sites involved or the location of each manifestation. Cases with both sensory and motor manifestations were less likely to have complete resolution than those with sensory or motor manifestations alone. Cases with manifestations involving the legs were less likely resolve completely than those with manifestations in the arms, especially if both sensory and motor manifestations were reported. Based on these data, a linear logistic model was developed to predict the probability of incomplete resolution after the first recompression treatment depending on the type and location of the manifestations.

Adolescent↗

PubMed1996

Relationship of the time course of venous gas bubbles to altitude decompression illness.

The correlation is low between the occurrence of gas bubbles in the pulmonary artery, called venous gas emboli (VGE), and subsequent decompression illness (DCI). The correlation improves when a "grade" of VGE is considered; a zero to four categorical classification based on the intensity and duration of the VGE signal from a Doppler bubble detector. Additional insight about DCI might come from an analysis of the time course of the occurrence of VGE. Using the NASA Hypobaric Decompression Sickness Databank, we compared the time course of the VGE outcome between 322 subjects who exercised and 133 Doppler technicians who did not exercise to evaluate the role of physical activity on the VGE outcome and incidence of DCI. We also compared 61 subjects with VGE and DCI with 110 subjects with VGE but without DCI to identify unique characteristics about the time course of the VGE outcome to try to discriminate between DCI and no-DCI cases. The VGE outcome as a function of time showed a characteristic short lag, rapid response, and gradual recovery phase that was related to physical activity at altitude and the presence or absence of DCI. The average time for DCI symptoms in a limb occurred just before the time of the highest fraction of VGE in the pulmonary artery. It is likely, but not certain, that an individual will report a DCI symptom if VGE are detected early in the altitude exposure, the intensity or grade of VGE rapidly increases from a limb region, and the intensity or grade of VGE remains high.

Adult↗

PubMed2003

Energy and the rate of evolution: inferences from plant rDNA substitution rates in the western Pacific.

In this study, we compare rDNA substitution rates for a group of closely related plant species in the western Pacific that exist in different biomes. The results of this comparison indicate higher rates of substitution for species living in habitats with greater biologically available energy. We interpret that finding as potentially important in understanding evolution because of its implication that substitution rate may be a function of biologically available energy and its correlate, productivity. The relevance of this research is twofold. First, contrasting closely related species across different biomes allows for a comparison between rates of molecular evolution across different energetic/productivity regimes while controlling for phylogenetically influenced variation. Second, the research indicates some of the design parameters for future studies that are required to explore the importance of this relationship among different groups of related organisms. If higher rates of molecular evolution where there is greater available energy are found to be widespread this might bring an additional dimension to the understanding of macroevolutionary pattern and process.

Australasia↗

PubMed2006

SAR image filtering based on the heavy-tailed Rayleigh model.

Synthetic aperture radar (SAR) images are inherently affected by a signal dependent noise known as speckle, which is due to the radar wave coherence. In this paper, we propose a novel adaptive despeckling filter and derive a maximum a posteriori (MAP) estimator for the radar cross section (RCS). We first employ a logarithmic transformation to change the multiplicative speckle into additive noise. We model the RCS using the recently introduced heavy-tailed Rayleigh density function, which was derived based on the assumption that the real and imaginary parts of the received complex signal are best described using the alpha-stable family of distribution. We estimate model parameters from noisy observations by means of second-kind statistics theory, which relies on the Mellin transform. Finally, we compare the proposed algorithm with several classical speckle filters applied on actual SAR images. Experimental results show that the homomorphic MAP filter based on the heavy-tailed Rayleigh prior for the RCS is among the best for speckle removal.

Algorithms↗

PubMed2005

Sensitivity analysis of discrete stochastic systems.

Sensitivity analysis quantifies the dependence of system behavior on the parameters that affect the process dynamics. Classical sensitivity analysis, however, does not directly apply to discrete stochastic dynamical systems, which have recently gained popularity because of its relevance in the simulation of biological processes. In this work, sensitivity analysis for discrete stochastic processes is developed based on density function (distribution) sensitivity, using an analog of the classical sensitivity and the Fisher Information Matrix. There exist many circumstances, such as in systems with multistability, in which the stochastic effects become nontrivial and classical sensitivity analysis on the deterministic representation of a system cannot adequately capture the true system behavior. The proposed analysis is applied to a bistable chemical system--the Schlögl model, and to a synthetic genetic toggle-switch model. Comparisons between the stochastic and deterministic analyses show the significance of explicit consideration of the probabilistic nature in the sensitivity analysis for this class of processes.

Algorithms↗

PubMedDate not supplied

A random graph model for the final-size distribution of household infections.

In epidemiological/disease control studies, one might be interested in estimating the parameters community probability infection (CPI) and the household secondary attack rate (SAR), as introduced by Longini and Koopman. The quasi-binomial distribution I (QBD I) with parameters n, p and theta, introduced by Consul, is proposed as a model for the final-size distribution of household infections, where p (CPI) is the probability of an individual being infected from the community and theta (SAR) is the rate of secondary transmission of infection within household. An individual can be infected either from within the household or from the community. Let X be the total number of infected members in a household of size n. Then the distribution of X is given by the QBD I with the probability mass function: (formula: see text) with 0 < p < 1, theta > or = 0 such that p + n theta < 1. The epidemic model is derived from a directed random graph. Data from influenza epidemics in Asian and American households are used to test the model and a comparison is made with the Longini-Koopman model. It is shown empirically that the QBD I is as good as the L-K model in describing the household infectious disease data, and both models provide almost identical estimates for community and household transmission parameters although they are derived from different perspectives and conditions.

Asia↗

PubMed2006

Multilocus linkage disequilibrium mapping of epistatic quantitative trait loci that regulate HIV dynamics: a simulation approach.

The time-dependent change of HIV particle load, i.e. HIV dynamics, is likely to be controlled by a multitude of quantitative trait loci (QTL) that interact with each other as well as with various developmental and environmental factors in a coordinated manner. In this article, we have derived a new statistical model for mapping the epistatic QTL responsible for HIV dynamics in a natural human population. This model, constructed on the integrated theme of functional mapping and linkage disequilibrium (LD) mapping, can make use of information from multiple markers genotyped from the human genome. It allows for the test and estimation of genetic actions and interactions involved in the control of HIV progression and provides a general platform to identify the detailed genetic architecture of resistance or susceptibility of humans to HIV on a dynamic scale. We have generalized this model to accommodate various complicated clincal designs for AIDS studies. Simulation studies with different scenarios are performed to examine the statistical behaviour of the model. The genetic and statistical extensions of this mapping model to HIV/AIDS genomic research are discussed.

Computer Simulation↗

PubMed2004

Evolution of vertebrate genes related to prion and Shadoo proteins--clues from comparative genomic analysis.

Recent findings of new genes in fish related to the prion protein (PrP) gene PRNP, including our recent report of SPRN coding for Shadoo (Sho) protein found also in mammals, raise issues of their function and evolution. Here we report additional novel fish genes found in public databases, including a duplicated SPRN gene, SPRNB, in Fugu, Tetraodon, carp, and zebrafish encoding the Sho2 protein, and we use comparative genomic analysis to analyze the evolutionary relationships and to infer evolutionary trajectories of the complete data set. Phylogenetic footprinting performed on aligned human, mouse, and Fugu SPRN genes to define candidate regulatory promoter regions, detected 16 conserved motifs, three of which are known transcription factor-binding sites for a receptor and transcription factors specific to or associated with expression in brain. This result and other homology-based (VISTA global genomic alignment; protein sequence alignment and phylogenetics) and context-dependent (genomic context; relative gene order and orientation) criteria indicate fish and mammalian SPRN genes are orthologous and suggest a strongly conserved basic function in brain. Whereas tetrapod PRNPs share context with the analogous stPrP-2-coding gene in fish, their sequences are diverged, suggesting that the tetrapod and fish genes are likely to have significantly different functions. Phylogenetic analysis predicts the SPRN/SPRNB duplication occurred before divergence of fish from tetrapods, whereas that of stPrP-1 and stPrP-2 occurred in fish. Whereas Sho appears to have a conserved function in vertebrate brain, PrP seems to have an adaptive role fine-tuned in a lineage-specific fashion. An evolutionary model consistent with our findings and literature knowledge is proposed that has an ancestral prevertebrate SPRN-like gene leading to all vertebrate PrP-related and Sho-related genes. This provides a new framework for exploring the evolution of this unusual family of proteins and for searching for members in other fish branches and intermediate vertebrate groups.

Animals↗

PubMed2005

Bayesian population dynamics of interacting species: great gerbils and fleas in Kazakhstan.

We propose a discrete-time Bayesian hierarchical model for the population dynamics of the great gerbil-flea ecological system. The model accounts for the sampling variability arising from data originally collected for other purposes. The prior for the unknown population densities incorporates specific biological hypotheses regarding the interacting dynamics of the two species, as well as their life cycles, where density-dependent effects are included. Posterior estimates are obtained via Markov chain Monte Carlo. The variance of the observed density estimates is a quadratic function of the unknown density. Our study indicates the presence of a density-dependent growth rate for the gerbil population. For the flea population there is clear evidence of density-dependent over-summer net growth, which is dependent on the flea-to-gerbil ratio at the beginning of the reproductive summer. Over-winter net growth is favored by high density. We estimate that on average 35% of the gerbil population survives the winter. Our study shows that hierarchical Bayesian models can be useful in extracting ecobiological information from observational data.

Animals↗

PubMed2004

Score tests of genetic association in the presence of linkage based on the additive genetic gamma frailty model.

Nuclear families with multiple affected sibs are often collected for genetic linkage analysis of complex diseases. Once linkage evidence is established, dense markers are often typed in the linked region for genetic association analysis based on linkage disequilibrium (LD). Detection of association in the presence of linkage localizes disease genes more accurately than the methods that rely on linkage alone. However, test of association due to LD in the linked region needs to account for dependency of the allele transmissions to different sibs within a family. In this paper, we define a joint model for genetic linkage and association and derive the corresponding joint survival function of age of onset for the sibs within a sibship. The joint survival function is a function of both the inheritance vector and the genotypes at the candidate marker locus. Based on this joint survival function, we derive score tests for genetic association. The proposed methods utilize the phenotype data of all the sibs and have the advantages of family-based designs which can avoid the potential spurious association caused by population admixture. In addition, the methods can account for variable age of onset or age at censoring and possible covariate effects, and therefore provide important tools for modelling disease heterogeneity. Simulation studies and application to the data sets from the 12th Genetic Analysis Workshop indicate that the proposed methods have correct type 1 error rates and increased power over other existing methods for testing allelic association.

Adult↗

PubMed2000

Neuropeptide Y receptor gene y6: multiple deaths or resurrections?

The neuropeptide Y family of G-protein-coupled receptors consists of five cloned members in mammals. Four genes give rise to functional receptors in all mammals investigated. The y6 gene is a pseudogene in human and pig and is absent in rat, but generates a functional receptor in rabbit and mouse and probably in the collared peccary (Pecari tajacu), a distant relative of the pig family. We report here that the guinea pig y6 gene has a highly distorted nucleotide sequence with multiple frame-shift mutations. One evolutionary scenario may suggest that y6 was inactivated before the divergence of the mammalian orders and subsequently resurrected in some lineages. However, the pseudogene mutations seem to be distinct in human, pig, and guinea pig, arguing for separate inactivation events. In either case, the y6 gene has a quite unusual evolutionary history with multiple independent deaths or resurrections.

Amino Acid Sequence↗

PubMed1998

Long-term results of ABO-incompatible living kidney transplantation: a single-center experience.

BACKGROUND: Despite great efforts to promote the donation of cadaveric organs, the number of organ transplantations in Japan is not increasing and a serious shortage of cadaveric organs exists. These circumstances have forced a widening of indications for kidney transplantation. For this purpose, ABO-incompatible living kidney transplantations (LKTs) have been performed. Although we have already reported the short-term results of ABO-incompatible LKT, there is no report of long-term results in such cases; anti-A and anti-B antibodies could cause antibody-induced chronic rejection and result in poor long-term graft survival. In this study, we have reviewed the long-term results of ABO-incompatible LKT and tried to identify the most important factors for long-term renal function in ABO-incompatible LKT. METHODS: Sixty-seven patients with end-stage renal failure underwent ABO-incompatible living kidney transplantation at our institute between January, 1989, and December, 1995. The mean age was 34.9 years (range, 8-58 years), with 38 males and 29 females. Incompatibility in ABO blood group antigens was as follows: A1-->O, 23 patients; B-->O, 19 patients; A1B-->A1, 7 patients; B-->A1, 8 patients; A1-->B; 4 patients; A1B-->B, 4 patients; A1B-->O, 2 patients. The number of HLA-AB, and -DR mismatches were 1.6+/-1.1 and 0.76+/-0.6, respectively. Plasmapheresis and immunoadsorption were carried out to remove the anti-AB antibodies before the kidney transplantation. In the induction phase, methylprednisolone, cyclosporine, azathioprine, antilymphocyte globulin, and deoxyspergualin were used for immunosuppression. Local irradiation of the graft was performed at a dose of 150 rad, on the first, third, and fifth days after transplantation. Splenectomy was done at the time of kidney transplantation in all cases. RESULTS: Patient survival was 93% at 1 year and 91% at 8 years. Graft survival was 79% at 1, 2, 3, and 4 years, 75% at 5 and 6 years, and 73% at 7 and 8 years. Patient survival was not significantly different from that of ABO-compatible patients. However, graft survival was significantly different between ABO-incompatible grafts and ABO-compatible grafts. Specifically, ABO-incompatible transplant recipients experienced a significantly higher rate of early graft loss up to 3 years but showed an equivalent graft loss by year 4. Among 67 patients, 16 grafts were lost during the observation period. Loss was due to acute rejection in 5 patients, followed by chronic rejection in 5 patients and death with function in 3 patients, whereas immunosuppression was withdrawn in 3 patients due to nonimmunological reasons. Of 16 grafts lost, 15 were lost within 1 year after transplantation. Of the 67 patients, 5 died during observation. Three patients with functioning grafts died of uncontrolled bleeding due to duodenal ulcer, malignant lymphoma, and cerebral hemorrhage (one patient each). One patient died of ischemic colitis due to secondary amyloidosis and one patient of cerebral hemorrhage after graft loss due to humoral rejection. There was no fatal infectious complication, whereas 10 patients had non-tissue-invasive cytomegalovirus infection. The stepwise logistic regression model was employed to identify the most important factors for long-term renal function. Patients were subdivided into those with serum creatinine of less than 2.0 mg/dl (group 1, n=39) versus those with serum creatinine of more than 2.0 mg/dl (group 2, n=22) at one year after renal transplantation. Six patients were excluded because of death with functioning graft (three patients) and withdrawal of immunosuppression (three patients). Rejection episodes within 6 months were significantly frequent in group 2 compared with group 1 (P=0.0008). Odds ratio was 112-fold in the rejection episodes. Obviously, the high incidence of early humoral rejection is caused by ABO incompatibility, because ABO-incompatible grafts experience a higher rate of early rejection and graft loss compa

ABO Blood-Group System↗