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A comparison between multivariate Slash, Student's t and probit threshold models for analysis of clinical mastitis in first lactation cows.

Robust threshold models with multivariate Student's t or multivariate Slash link functions were employed to infer genetic parameters of clinical mastitis at different stages of lactation, with each cow defining a cluster of records. The robust fits were compared with that from a multivariate probit model via a pseudo-Bayes factor and an analysis of residuals. Clinical mastitis records on 36 178 first-lactation Norwegian Red cows from 5286 herds, daughters of 245 sires, were analysed. The opportunity for infection interval, going from 30 days pre-calving to 300 days postpartum, was divided into four periods: (i) -30 to 0 days pre-calving; (ii) 1-30 days; (iii) 31-120 days; and (iv) 121-300 days of lactation. Within each period, absence or presence of clinical mastitis was scored as 0 or 1 respectively. Markov chain Monte Carlo methods were used to draw samples from posterior distributions of interest. Pseudo-Bayes factors strongly favoured the multivariate Slash and Student's t models over the probit model. The posterior mean of the degrees of freedom parameter for the Slash model was 2.2, indicating heavy tails of the liability distribution. The posterior mean of the degrees of freedom for the Student's t model was 8.5, also pointing away from a normal liability for clinical mastitis. A residual was the observed phenotype (0 or 1) minus the posterior mean of the probability of mastitis. The Slash and Student's t models tended to have smaller residuals than the probit model in cows that contracted mastitis. Heritability of liability to clinical mastitis was 0.13-0.14 before calving, and ranged from 0.05 to 0.08 after calving in the robust models. Genetic correlations were between 0.50 and 0.73, suggesting that clinical mastitis resistance is not the same trait across periods, corroborating earlier findings with probit models.

Animals↗

Ultrasonic and biochemical evaluation of human diabetic lens.

OBJECTIVE: To evaluate the ultrasonic attenuation and amount of soluble proteins of human diabetic lens. MATERIALS AND METHODS: The examination was performed in the Clinic of Eye Diseases of Kaunas University of Medicine. The study included 4 groups of patients (110 eyes). The first group consisted of healthy subjects (32 eyes), the second group--of patients with initial senile cataract (13 eyes), the third group--patients with type I diabetes mellitus (24 eyes) and the fourth group--patients with type II diabetes mellitus (41 eyes). In vivo examination of human lenses was carried out by Mentor A/B ultrasonic imaging system using 7 MHz A-mode probe and the ultrasound attenuation coefficient was calculated. The phacoemulsification technique has been used for cataract extraction. Gel chromatography of the supernatant fraction on the Sepharose CL 6B column was used for fractionation of soluble lens proteins. Protein concentration was determined by the method of Lowry using bovine serum as standard. RESULTS: The least mean lens thickness of 3.58+/-0.18 mm was found in the healthy patients' group. There was a significant difference (p<0.05) between the thicknesses of the lenses in the healthy group and in the type I diabetic group. The difference between senile cataract and type II diabetic cataract was insignificant (p>0.05). The mean ultrasound attenuation coefficient in the groups of healthy and type I diabetic cataract was nearly the same, as so as in the groups of senile cataract and type II diabetic cataract. The significant difference (p<0.001) in the values of attenuation coefficient was found between the groups of type I and type II diabetics. The amount of soluble proteins was lowest in cataractous lenses of patients with type II diabetes (0.053+/-0.007 mg/1 mg tissue) and highest in the lenses of patients with type I diabetes (0.063+/-0.004 mg / 1 mg tissue), but those differences were statistically insignificant. Distribution of soluble proteins into the different molecular mass fractions in the group of type I diabetic lenses was found to be similar to the type II diabetic lenses and to the patients with senile cataract. CONCLUSIONS: The diabetic changes stronger influence the thickness of lenses of young people; in the elder age the difference between the thickness of senile and diabetic cataract is not so distinct. Ultrasound attenuation coefficient has a tendency to be higher in patients with senile and type II diabetic cataract. Human lens crystallins of patients with type I diabetes and type II diabetes are damaged at the same degree, the amount of soluble proteins decrease with age and biochemical changes of the lens.

Adult↗

Size frequency distribution of prion protein (PrP) aggregates in variant Creutzfeldt-Jakob disease (vCJD).

The frequency distribution of aggregate size of the diffuse and florid-type prion protein (PrP) plaques was studied in various brain regions in cases of variant Creutzfeldt-Jakob disease (vCJD). The size distributions were unimodal and positively skewed and resembled those of beta-amyloid (A beta) deposits in Alzheimer's disease (AD) and Down's syndrome (DS). The frequency distributions of the PrP aggregates were log-normal in shape, but there were deviations from the expected number of plaques in specific size classes. More diffuse plaques were observed in the modal size class and fewer in the larger size classes than expected and more florid plaques were present in the larger size classes compared with the log-normal model. It was concluded that the growth of the PrP aggregates in vCJD does not strictly follow a log-normal model, diffuse plaques growing to within a more restricted size range and florid plaques to larger sizes than predicted.

Adolescent↗

Imbalanced distribution of Plasmodium falciparum EBA-175 genotypes related to clinical status in children from Bakoumba, Gabon.

OBJECTIVE: The erythrocyte binding antigen 175 kDa (EBA-175) of Plasmodium falciparum is one of the major ligands for red blood cell invasion by merozoites. EBA-175 is a dimorphic antigen but the role that dimorphism plays in host parasite interaction is not fully understood. In this study, we sought to determine the distribution of EBA-175 genotypes and its pathogenetic influence. METHODS: The nested polymerase chain reaction was used to determine the genotypes of P. falciparum isolates from asymptomatic and symptomatic Gabonese children. RESULTS: CAMP strains (C-segment) and FCR-3 strains (F-segment) were found in 13/50 (26%) and 19/50 (38%) symptomatic children, respectively and in 16/66 (24%) and 46/66 (70%) asymptomatic children, respectively. The prevalence of mixed C-/F- infection was 18/50 (36%) and 4/66 (6%) in symptomatic and asymptomatic children, respectively. CONCLUSIONS: These results show that mixed C-/F- infection is associated with clinical malaria (chi2, P <0.01) and may have important therapeutic implications.

Adolescent↗

Assessment of agreement under nonstandard conditions using regression models for mean and variance.

The total deviation index of Lin and Lin et al. is an intuitive approach for the assessment of agreement between two methods of measurement. It assumes that the differences of the paired measurements are a random sample from a normal distribution and works essentially by constructing a probability content tolerance interval for this distribution. We generalize this approach to the case when differences may not have identical distributions -- a common scenario in applications. In particular, we use the regression approach to model the mean and the variance of differences as functions of observed values of the average of the paired measurements, and describe two methods based on asymptotic theory of maximum likelihood estimators for constructing a simultaneous probability content tolerance band. The first method uses bootstrap to approximate the critical point and the second method is an analytical approximation. Simulation shows that the first method works well for sample sizes as small as 30 and the second method is preferable for large sample sizes. We also extend the methodology for the case when the mean function is modeled using penalized splines via a mixed model representation. Two real data applications are presented.

Likelihood Functions↗

[Sonographically detectable changes in placental structures in pregnancy. 3. Statistical, comparison of the frequency distribution of placenta stages 0-3 in newborn infants with a birth weight of less than 2,500 grams].

The utilisation of sonographically provable changes of placental structures in 131 pregnant woman (277 examinations) shows in cases with newborn infants with a weight of birth under 2500 gram than the stage 0 is found significant frequent to the 32. week of pregnancy, the stage 1 to the 40. week of pregnancy, the stage 2 between the 29. and 40. week of pregnancy and the stage 3 between the 31. and 40. week of pregnancy. The stages 0, 1 and 2 influence in comparison with the newborn infants with a weight of birth between 2500 gram and 3999 gram not the weight in newborn infants under 2500 gram. The stage 3 will prove frequent in 13,5 times before the 34. week of pregnancy as in the comparison group with normal weight of birth.

Birth Weight↗

Replication of linkage studies of complex traits: an examination of variation in location estimates.

In linkage studies, independent replication of positive findings is crucial in order to distinguish between true positives and false positives. Recently, the following question has arisen in linkage studies of complex traits: at what distance do we reject the hypothesis that two location estimates in a genomic region represent the same gene? Here we attempt to address this question. Sampling distributions for location estimates were constructed by computer simulation. The conditions for simulation were chosen to reflect features of "typical" complex traits, including incomplete penetrance, phenocopies, and genetic heterogeneity. Our findings, which bear on what is considered a replication in linkage studies of complex traits, suggest that, even with relatively large numbers of multiplex families, chance variation in the location estimate is substantial. In addition, we report evidence that, for the conditions studied here, the standard error of a location estimate is a function of the magnitude of the expected LOD score.

Chromosome Mapping↗

Optimal design for dose response using beta distributed responses.

Whenever a response is naturally confined to a finite interval (such as a visual analog scale for pain severity), the beta distribution provides a simple and flexible probability distribution to model such a response. The parameters of the distribution can then be related to covariates, such as dose, in a clinical trial through the generation of a beta regression model. In this article, we explore locally optimal designs for this class of regression models, focusing mainly on minimization of the generalized variance of maximum likelihood estimators (D-optimality). Optimal designs and sensitivity to misspecification of model parameters are examined using a candidate points searching algorithm. Although formally the model assumes that the response is continuous, it provides a parsimonious approximation for ordinal data when there is a relatively large number of categories. The resulting estimators and optimal designs are simpler and may offer more ease in interpretation than those derived from models for ordered categorical outcomes. The proposed methods are applied to data from a clinical trial.

Clinical Trials as Topic↗

Modeling the survival of Salmonella spp. in chorizos.

The survival of Salmonella spp. in chorizos has been studied under the effect of storage conditions; namely temperature (T=6, 25, 30 degrees C), air inflow velocity (F=0, 28.4 m/min), and initial water activity (a(w0)=0.85, 0.90, 0.93, 0.95, 0.97). The pH was held at 5.0. A total of 20 survival curves were experimentally obtained at various combinations of operating conditions. The chorizos were stored under four conditions: in the refrigerator (Ref: T=6 degrees C, F=0 m/min), at room temperature (RT: T=25 degrees C, F=0 m/min), in the hood (Hd: T=25 degrees C, F=28.4 m/min), and in the incubator (Inc: T=30 degrees C, F=0 m/min). Semi-logarithmic plots of counts vs. time revealed nonlinear trends for all the survival curves, indicating that the first-order kinetics model (exponential distribution function) was not suitable. The Weibull cumulative distribution function, for which the exponential function is only a special case, was selected and used to model the survival curves. The Weibull model was fitted to the 20 curves and the model parameters (alpha and beta) were determined. The fitted survival curves agreed with the experimental data with R(2)=0.951, 0.969, 0.908, and 0.871 for the Ref, RT, Hd, and Inc curves, respectively. Regression models relating alpha and beta to T, F, and a(w0) resulted in R(2) values of 0.975 for alpha and 0.988 for beta. The alpha and beta models can be used to generate a survival curve for Salmonella in chorizos for a given set of operating conditions. Additionally, alpha and beta can be used to determine the times needed to reduce the count by 1 or 2 logs t(1D) and t(2D). It is concluded that the Weibull cumulative distribution function offers a powerful model for describing microbial survival data. A comparison with the pathogen modeling program (PMP) revealed that the survival kinetics of Salmonella spp. in chorizos could not be adequately predicted using PMP which underestimated the t(1D) and t(2D). The mean of the Weibull probability density function correlated strongly with t(1D) and t(2D), and can serve as an alternative to the D-values normally used with first-order kinetic models. Parametric studies were conducted and sensitivity of survival to operating conditions was evaluated and discussed in the paper. The models derived herein provide a means for the development of a reliable risk assessment system for controlling Salmonella spp. in chorizos.

Animals↗

Modeling accident frequencies as zero-altered probability processes: an empirical inquiry.

This paper presents an empirical inquiry into the applicability of zero-altered counting processes to roadway section accident frequencies. The intent of such a counting process is to distinguish sections of roadway that are truly safe (near zero-accident likelihood) from those that are unsafe but happen to have zero accidents observed during the period of observation (e.g. one year). Traditional applications of Poisson and negative binomial accident frequency models do not account for this distinction and thus can produce biased coefficient estimates because of the preponderance of zero-accident observations. Zero-altered probability processes such as the zero-inflated Poisson (ZIP) and zero-inflated negative binomial (ZINB) distributions are examined and proposed for accident frequencies by roadway functional class and geographic location. The findings show that the ZIP structure models are promising and have great flexibility in uncovering processes affecting accident frequencies on roadway sections observed with zero accidents and those with observed accident occurrences. This flexibility allows highway engineers to better isolate design factors that contribute to accident occurrence and also provides additional insight into variables that determine the relative accident likelihoods of safe versus unsafe roadways. The generic nature of the models and the relatively good power of the Vuong specification test used in the non-nested hypotheses of model specifications offers roadway designers the potential to develop a global family of models for accident frequency prediction that can be embedded in a larger safety management system.

Accidents, Traffic↗

Are the common reference intervals truly common? Case studies on stratifying biochemical reference data by countries using two partitioning methods.

The Harris-Boyd method, recommended for partitioning biochemical reference data into subgroups by the NCCLS, and a recently proposed new method for partitioning were compared in three case studies concerning stratification by countries (Denmark, Finland, Norway, and Sweden) of reference data collected in the Nordic Reference Interval Project (NORIP) for the enzymes alkaline phosphatase (ALP), creatine kinase (CK), and gamma-glutamyl transpeptidase (GGT). The new method is based on direct estimation of the proportions of two subgroups outside the reference limits of the combined distribution, while the Harris-Boyd method uses easy-to-calculate test parameters as correlates for these proportions. The decisions on partitioning suggested by the Harris-Boyd method deviated from those obtained by using the new method for each of the three enzymes when considering pair-wise partitioning tests. The reasons for the poor performance, as it seems to be, of the Harris-Boyd method were discussed. Stratification of reference data into more than two subgroups was considered as both a theoretical problem and a practical one, using the four country-specific distributions for each enzyme as illustration. Neither the Harris-Boyd method nor the new method seems ideal to solve the partitioning problem in the case of several subgroups. The results obtained by using prevalence-adjusted values for the proportions seemed, however, to warrant the conclusion to be made that there are no major differences in terms of the partitioning criteria between the levels of each of the three enzymes in the four countries. Because these three enzymes include those two tests (CK, GGT), which in the preliminary analyses of the project data had shown largest variation between countries, the tentative conclusion was drawn that application of common reference intervals in the Nordic countries is feasible, not only for the three enzymes examined in the present study but for all of the tests involved in the NORIP project.

Chemistry, Clinical↗

A new clinical score for disease activity in Langerhans cell histiocytosis.

OBJECTIVE: To develop an objective tool for assessing disease activity in patients with Langerhans cell histiocytosis (LCH). METHOD: Scoring system was developed and applied to a database containing information on 612 patients. RESULTS: At diagnosis, the score distribution was highly asymmetrical: the score was between 0 and 2 in 74% of cases, 3-6 in 16%, 7-10 in 3%, and more than 10 in 6%. The 5-year mortality rates were 1, 4.4, and 43.4%, respectively, among patients with initial scores of 0-2, 3-6, and >6. Stability or an increase of the score at 6 weeks was highly predictive of death among patients with initial scores above 6, while score stability had no significant impact on vital outcome among patients with low or moderate scores at diagnosis. CONCLUSIONS: This LCH disease activity score provides an objective tool for assessing disease severity, both at diagnosis and during follow-up and treatment.

Antineoplastic Combined Chemotherapy Protocols↗

The distribution of the maximum likelihood estimator in up-and-down experiments for quantal dose-response data.

Standard maximum likelihood logistic or probit regression has been used in biopharmaceutical practice for inference about tolerance threshold distributions in situations where subjects (patients) have been allocated doses according to an up-and-down design. For example, a steeper dose-response curve than expected was reported in one such study. This article demonstrates that the maximum likelihood estimator systematically and considerably exaggerates the regression parameter with moderately large sample sizes. Thus a probable explanation for finding a steeper curve than expected is the method used to analyze the experiment, that is, the bias in the maximum likelihood estimator. An additional consequence of this bias is that the mean/median/ED50 are estimated with a misleading precision. In particular, confidence intervals are much too narrow. As a conclusion, we warn against conventional logistic or probit regression in combination with up-and-down designs.

Animals↗

A robust procedure for removing background damage in assays of radiation-induced DNA fragment distributions.

The non-random distribution of DNA breakage in PFGE (pulsed-field gel electrophoresis) experiments poses a problem of proper subtraction of the background DNA damage to obtain a fragment-size distribution due to radiation only. A naive bin-to-bin subtraction of the background signal will not result in the right DNA mass distribution histogram. This problem could become more pronounced for high-LET (linear energy transfer) radiation, because the fragment-size distribution manifests a higher frequency of smaller fragments. Previous systematic subtraction methods have been based on random breakage, appropriate for low-LET radiation. Moreover, an investigation is needed to determine whether the background breakage is itself random or non-random. We consider two limiting cases: (1) the background damage is present in all cells, and (2) it is present in only a small subset of cells, while other cells are not contributing to the background DNA fragmentation. We give a generalized formalism based on stochastic processes for the subtraction of the background damage in PFGE experiments for any LET and apply it to two sets of PFGE data for iron ions.

Algorithms↗

Three-base periodicity patterns and self-similarity in whole bacterial chromosomes.

It has been reported that in a collection of mRNAs the triplets GhN or RNY had a higher propensity to be separated by either three/six/nine, etc., bases than by two/four/five, etc., bases. This has been called three-base periodicity (TBP). In this work the frequency distribution of distances (FDDs) for all triplets in the Borrelia burgdorferi chromosome and selected triplets in other model sequences were determined. The FDDs produced oscillatory decaying patterns with TBP for most triplets and not only for those encompassed by the above formulas. Furthermore, we also found TBP for di- and mononucleotides. However, TBP was not observed for intergenic regions, sequences with a low content of coding regions or when the coding potential of sequences was disrupted by base shuffling. Excluding closely related species the FDDs between bacterial genomes were different and appeared characteristic of the analyzed genome. FDDs also showed self-similarity, since 1Mb sequences rendered FDDs that were very similar to those for the entire sequence.

Base Composition↗

Body weight and the shape of the natural distribution of weight, in very large samples of German, Austrian and Norwegian conscripts.

OBJECTIVE: To investigate the shape of the natural distribution of body weight in conscripts. DESIGN: Investigation of weight and weight distributions in German, Austrian and Norwegian conscripts. SUBJECTS: A total of 10 706 651 West German conscripts (30 birth cohorts born between 1938 and 1971, except for the cohorts born 1941-1944), 507 095 Austrian conscripts (10 birth cohorts born between 1966 and 1975), and 27 311 Norwegian conscripts (1997 conscription). RESULTS: In Germans, average body weight increased by 100 g/y up to birth cohort 1965, thereafter by 400 g/y, and by 200 g/y in Austrians. Body weight is not normally distributed, but skewed to the right. Also power transformation was inadequate to sufficiently describe the shape of this distribution. The right tail of weight distributions declines exponentially, beyond a cut-off of +0.5 standard deviations. There is a strong relation between average weight and the prevalence of obesity, except for those cohorts that suffered from severe starvation (1945-1948) during early and mid-childhood. These cohorts appeared to be more resistant against obesity. CONCLUSION: Obesity appears to be a characteristic feature of a population as a whole, and does not seem to be a separate problem of only the obese people. It may be questioned whether (in terms of public health) the optimal solution for treating obesity is treating the obese people, or whether one should consider measures to reduce average weight in a population instead, as this might reduce the number obese people and the severity of the illness.

Austria↗

Fine-scale distribution of pine ectomycorrhizas and their extramatrical mycelium.

In order to clarify the functional role of individual ectomycorrhizal (EcM) fungal species in the field, we need to relate their abundance and distribution as mycorrhizas to their abundance and distribution as extramatrical mycelium (EMM). We divided each of four 20 cm x 20 cm x 2 cm slices of pine forest soil into 100 cubes of 2 cm x 2 cm. For each cube, ectomycorrhizas were identified and the presence of EMM of the EcM fungi recorded as ectomycorrhizas was determined by terminal restriction fragment length polymorphism (T-RFLP) analysis of ITS rDNA. Ectomycorrhizas and EMM of seven EcM species were mapped. Spatial segregation of mycorrhizas and EMM was evident and some species produced their EMM in different soil layers from their mycorrhizas. The spatial relationship between mycorrhizas and their EMM generally conformed to their reported exploration types, but EMM of smooth types (e.g. Lactarius rufus) was more frequent than expected. Different EcM fungi foraged at different spatial scales.

Ascomycota↗

Parameter distribution models for estimation of population based left ventricular deformation using sparse fiducial markers.

We present a method to estimate left ventricular (LV) motion based on three-dimensional (3-D) images that can be derived from any anatomical tomographic or 3-D modality, such as echocardiography, computed tomography, or magnetic resonance imaging. A finite element mesh of the LV was constructed to fit the geometry of the wall. The mesh was deformed by optimizing the nodal parameters to the motion of a sparse number of fiducial markers that were manually tracked in the images through the cardiac cycle. A parameter distribution model (PDM) of LV deformations was obtained from a database of MR tagging studies. This was used to filter the calculated deformation and incorporate a priori information on likely motions. The estimated deformation obtained from 13 normal untagged studies was compared with the deformation obtained from MR tagging. The end systolic (ES) circumferential and longitudinal strain values matched well with a mean difference of 0.1 +/- 3.2% and 0.3 +/- 3.0%, respectively. The calculated apex-base twist angle at ES had a mean difference of 1.0 +/- 2.3 degrees. We conclude that fiducial marker fitting in conjunction with a PDM provides accurate reconstruction of LV deformation in normal subjects.

Adult↗