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Results for “Likelihood Functions”

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PubMed1999

99mTc-tetrofosmin SPECT for prediction of functional recovery defined by MRI in patients with severe left ventricular dysfunction: additional value of gated SPECT.

UNLABELLED: This study was designed to evaluate gated 99mTc-tetrofosmin SPECT for prediction of functional recovery proven by sequential MRI. 99mTc-labeled tetrofosmin is a recently introduced tracer for myocardial perfusion. However, its role for viability assessment is still under investigation. METHODS: 99mTc-tetrofosmin uptake in 19 patients with coronary artery disease and severe left ventricular dysfunction was correlated to regional wall thickening before and 4.5 +/- 0.8 mo after successful coronary artery bypass grafting, as derived from corresponding gated short-axis MRI. Preoperative wall thickening determined by gated SPECT was used as an additional parameter for prediction of functional outcome. Optimal threshold cutoffs to separate reversible from irreversible dysfunction were determined by receiver operator characteristic (ROC) analysis. RESULTS: The sensitivity and specificity of regional 99mTc-tetrofosmin for prediction of functional recovery was 87% and 42%, respectively (cutoff: 50% of maximum tracer retention). The area under ROC curves for prediction of functional recovery measured 0.66 +/- 0.01. Segments with > or =50% uptake and impaired but detectable wall thickening determined by gated SPECT had a significantly higher likelihood for functional improvement compared with segments with absent wall thickening (P < 0.05). There was no difference in segments with <50% tracer retention. There was good agreement for ejection fraction measurements by MRI and gated SPECT (mean ejection fraction 32 +/- 12 versus 34 +/- 11; r = 0.71, P < 0.001). CONCLUSION: Regional 99mTc-tetrofosmin uptake provided high sensitivity but limited specificity for prediction of functional recovery after revascularization, leading to fair overall accuracy. Wall thickening assessment derived from gated SPECT may improve the specificity of 99mTc-tetrofosmin uptake for prediction of functional recovery but not the sensitivity in low-flow areas. In addition to the assessment of global function, gated data acquisition can be helpful to improve the overall accuracy of 99mTc-tetrofosmin SPECT for prediction of functional recovery after bypass surgery.

Coronary Artery Bypass↗

PubMed1998

Modeling hazard functions in families.

A genetic frailty model is presented for censored age of onset data in nuclear families where individuals carrying a genetic susceptibility gene have an increased risk of becoming affected. We use maximum likelihood via the EM algorithm to estimate the genetic relative risk and the allele frequency under a dominant susceptibility type and a proportional hazards model. When sampling is from a disease registry, likelihood corrections are necessary for reducing bias in the parameter estimates. In these biased samples, the full conditional likelihood is approximated by a likelihood conditional on the proband's age of onset. For unbiased samples, simulations show the distributions of the estimates are similar under both a semiparametric and the correctly specified parametric likelihoods. For biased samples, simulations under the approximate conditional likelihood show the median estimates of the allele frequency and genetic relative risk tend to under- and overestimate, respectively, the true values; however, the approximation is better for rarer allele frequencies (0.0033 vs. 0.01). In practice, large samples or more complex ascertainment corrections are recommended. Using the approximate conditional likelihood on familial breast cancer onset data collected as part of a case-control study at the Fred Hutchinson Cancer Research Center in Seattle, Washington, we estimate an allele frequency of 0.0009 (approximate 95% CI 0.0006-0.002) and a genetic relative risk of 104 (approximate 95% CI 55-181).

Adolescent↗

PubMedDate not supplied

Time series for modelling counts from a relapsing-remitting disease: application to modelling disease activity in multiple sclerosis.

Many chronic diseases are relapsing-remitting diseases, in which subjects alternate between periods with increasing and decreasing disease activity; relapsing-remitting multiple sclerosis is an example. This paper proposes two classes of models for sequences of counts observed from a relapsing-remitting disease. In the first, the relapsing-remitting nature of the data is modelled by a Poisson time series with a periodic trend in the mean. In this approach, the mean is expressed as a function of a sinusoidal trend and past observations of the time series. An algorithm that uses GLIM is developed, and it results in maximum-likelihood estimation for the amplitude, frequency and autoregressive effects. In the second class of models, the relapsing-remitting behaviour is described by a Poisson time series in which changes in the mean follow a latent Markov chain. An EM algorithm is developed for maximum-likelihood estimation for this model. The two models are illustrated and compared with data from a study evaluating the use of serial magnetic resonance imaging as a measure of disease activity in relapsing-remitting multiple sclerosis.

Algorithms↗

PubMed2004

[Coronary risk assessment in subjects with type 2 diabetes mellitus. General population-based scores or specific scores?].

Coronary risk in patients with type 2 diabetes mellitus can be calculated using population-based scores or diabetes-specific scores. Our objective was to compare the results with both scores in a group of patients with type 2 diabetes and no history of cardiovascular disease. We analyzed the results for 101 patients aged 40 to 65 years with type 2 diabetes and no prior cardiovascular disease. Two scales were used, one based on the general population (Framingham function adapted from the REGICOR study), and the other based on the population with type 2 diabetes mellitus (UKPDS risk engine). The average 10-year likelihood of coronary events was 5.8 (2.5)% and 15.7 (8.4)% for the REGICOR risk score and the UKPDS risk score, respectively (P<.001), with a Pearson correlation coefficient of 0.525 (P<.01). Risk was higher in men (19.2 [8.7]% based on the UKPDS score, and 5.6 [2.8]% based on the REGICOR score, P<.001). The figures for women were 11.3 [5.9]% and 5.9 [2.1]% with the UKPDS and REGICOR scores, respectively (P<.001). Our results suggest that substantially different findings are obtained when general population-based scores or specific scores are used to assess cardiovascular risk in subjects with type 2 diabetes.

Adult↗

PubMed2005

Plant photoreceptors: phylogenetic overview.

Plants possess photoreceptors to perceive light which controls most aspects of their lives. Three photoreceptor families are well characterized: cryptochromes (crys), phototropins (phots), and phytochromes (phys). Two putative families have been identified more recently: Zeitlupes (ZTLs) and UV-B photoreceptors (ULI). Using Arabidopsis thaliana and Oryza sativa photoreceptor sequences as references, we have searched for photoreceptor encoding genes in the major phyla of plant kingdom. For each photoreceptor family, using a phylogenetic tree based on the alignment of conserved amino acid sequences, we have tried to trace back the evolution and the emergence of the diverse photoreceptor ancestral sequences. The green alga Chlamydomonas contains one cry and one phot sequence, probably close to the corresponding ancestral sequences, and no phy-related sequence. The putative UV-B photoreceptors seem to be restricted to the Brassicacae. Except for mosses and ferns, which contain divergent photoreceptor numbers, the composition of the diverse photoreceptor families is conserved between species. A high conservation of the residues within domains is observed in each photoreceptor family. The complete phylogenic analysis of the photoreceptor families in plants has confirmed the existence of crucial evolutionary nodes between the major phyla. For each photoreceptor class, a major duplication occurred before the separation between Mono- and Eudicotyledons. This allowed postulating on the putative ancestral function of the photoreceptors.

Amino Acid Sequence↗

PubMed2006

Bovine seminal plasma proteins and their relatives: A new expanding superfamily in mammals.

BSP proteins represent three major proteins of bovine seminal plasma: BSP-A1/-A2, -A3 and -30 kDa. The BSP protein signature is characterized by two tandemly repeated fibronectin type 2 (Fn2) domains. Although classical affinity chromatography and protein sequencing have proven that the BSP protein homologs may be ubiquitous in mammals and functionally related to sperm capacitation, only the three bovine genes have been reported thus far. In this study, we report three new BSP protein-related genes from bovine, as well as other BSP protein-related DNA sequences from human, chimpanzee, mouse, rat, dog, horse and rabbit. Analysis of the relationships between all Fn2 domain-containing proteins revealed that the Fn2 domains found in BSP-related proteins have special features that distinguish them from non-BSP-related proteins. These features can be used to identify new BSP protein-related sequences. Further molecular evolutionary analysis of the BSP protein lineage revealed that all BSP proteins and their related sequences can be grouped into three subfamilies: BSPH4, BSPH5 and BSPH6, which indicates that the BSP protein family is much bigger than previously envisioned. More interestingly, the three BSP proteins in bovine within the BSPH4-subfamily were shown to evolve rapidly. The ratio of nonsynonymous to synonymous substitutions was higher than 1. The analysis also indicated that the rate of evolution was heterogeneous between the first and second Fn2 domains of the genes. These data may reflect that some amino acids in BSP proteins are under a strong positive selection after gene duplication and that each BSP protein evolves rapidly, possibly to acquire new functions.

Amino Acid Sequence↗

PubMed2000

Selective constraints, amino acid composition, and the rate of protein evolution.

What are the major forces governing protein evolution? A common view is that proteins with strong structural and functional requirements evolve more slowly than proteins with weak constraints, because a stringent negative selection pressure limits the number of substitutions. In contrast, Graur claimed that the substitution rate of a protein is mainly determined by its amino acid composition and the changeabilities of amino acids. In this paper, however, we found that the relative changeabilities of amino acids in mammalian proteins are different for transmembranal and nontransmembranal segments, which have very distinct structural requirements. This indicates that the changeability of a given residue is influenced by the structural and functional context. We also reexamined the relationship between substitution rate and amino acid composition. Indeed, the two kinds of segments exhibit contrasting amino acid compositions: transmembranal regions are made up mainly of hydrophobic residues (a total frequency of approximately 60%) and are very poor in polar amino acids (<5%), whereas nontransmembranal segments have frequencies of 30% and 22%, respectively. Interestingly, we found that within a given integral membrane protein, nontransmembranal segments accumulate, on average, twice as many substitutions as transmembranal regions. However, regression analyses showed that the variability in amino acid frequencies among proteins cannot explain more than 30% of the variability in substitution rate for the transmembranal and nontransmembranal data sets. Furthermore, transmembranal and nontransmembranal segments evolving at the same rate in different proteins have different compositions, and the compositions of slowly evolving and rapidly evolving segments of the same type are similar. From these observations, we conclude that the rate of protein evolution is only weakly affected by amino acid composition but is mostly determined by the strength of functional requirements or selective constraints.

Amino Acid Substitution↗

PubMed1999

Interval-censored survival data with informative examination times: parametric models and approximate inference.

We develop parametric methods for analysing interval-censored data when examination and survival times are not independent. The hazard function is modelled by introducing individual frailties related to the frequency of examinations. Model parameters may be obtained by direct maximization of the marginal log-likelihood. We develop a simpler approximate method in which the frailties are estimated by empirical Bayes. The two approaches are equivalent asymptotically as the number of examinations on each individual increases. Simulations suggest that the approximate method is adequate for estimating regression parameters even when the number of examinations on each individual is small. The methods are used to estimate age and period effects on HIV incidence in a cohort of repeat attenders at genito-urinary clinics in London, U.K.

Adult↗

PubMed1994

Estimating multiple tumor transition rates based on data from survival-sacrifice experiments.

The development of two types of tumors in an animal survival-sacrifice experiment can be described by a Markov illness-and-death process with four unknown tumor transition rates and four unknown death rates. Due to the occult nature of tumors, these transition rates cannot be identified through the use of a completely nonparametric model. We propose a semiparametric model that assumes that the four tumor transition rates are proportional to each other and can be described by a known parametric function. We show that these tumor transition rates can be estimated using an ECM algorithm and that inferences about these parameters can be drawn using the likelihood ratio test. We illustrate this model and the algorithm with data from the ED01 study.

Algorithms↗

PubMed2006

Ancestral reconstruction of the ligand-binding pocket of Family C G protein-coupled receptors.

The metabotropic glutamate receptors (mGluRs) within the Family C subclass of G protein-coupled receptors are crucial modulators of synaptic transmission. However, their closest relatives include a diverse group of sensory receptors whose biological functions are not associated with neurotransmission, raising the question of the evolutionary origin of amino acid-binding Family C receptors. A common feature of most, if not all, functional Family C receptors is the presence of an amino acid-binding site localized within the large extracellular Venus flytrap domain. Here, we used maximum likelihood methods to infer the ancestral state of key residues in the amino acid-binding pocket of a primordial Family C receptor. These residues were reconstructed in the background of the fish 5.24 chemosensory receptor, a broad-spectrum amino acid-activated receptor. Unlike the WT 5.24 receptor, which was not activated by mGluR agonists and displayed low sensitivity toward l-glutamate, the reconstructed ancestral receptor possessed a pharmacological profile characterized by high affinity for both l-glutamate and selective Group I mGluR agonists. This pharmacological phenotype could be largely recapitulated by mutating only two residues in the 5.24 receptor-binding pocket. Our results suggest that this primordial Family C receptor may have arisen early in metazoan evolution and that it already was preadapted as a glutamate receptor for its later use at excitatory synapses in glutamate-mediated neurotransmission.

Animals↗

PubMed2004

Comparative methods for the analysis of gene-expression evolution: an example using yeast functional genomic data.

Understanding the evolution of gene function is a primary challenge of modern evolutionary biology. Despite an expanding database from genomic and developmental studies, we are lacking quantitative methods for analyzing the evolution of some important measures of gene function, such as gene-expression patterns. Here, we introduce phylogenetic comparative methods to compare different models of gene-expression evolution in a maximum-likelihood framework. We find that expression of duplicated genes has evolved according to a nonphylogenetic model, where closely related genes are no more likely than more distantly related genes to share common expression patterns. These results are consistent with previous studies that found rapid evolution of gene expression during the history of yeast. The comparative methods presented here are general enough to test a wide range of evolutionary hypotheses using genomic-scale data from any organism.

Evolution, Molecular↗

PubMed2004

Perceived cognitive function is a major determinant of health related quality of life in a non-selected population of patients with coronary artery disease--a principal components analysis.

OBJECTIVE: To assess health related quality of life (HRQL) and explore its underlying structure in a non-selected population of patients with coronary artery disease (CAD). DESIGN, SETTING AND SUBJECTS: HRQL was estimated by the disease specific Cardiac Health Profile (CHP) questionnaire and the EuroQol-VAS (EQ) in 253 consecutive unselected CAD patients in Södertälje, Stockholm County, Sweden. Explorative factor analysis was used to identify independent dimensions of HRQL. Current angina was ranked according to Canadian Cardiovascular Society Classification (CCS). RESULTS: Four independent principal factors representing perceived cognitive, physical, social and emotional functions underlying the patients' HRQL were found. Identical factors were recognized with an alternate technique. The major factor--explaining 43 % of HRQL--was perceived cognitive function reflecting ability to concentrate, activity drive, memory and problem solving. Cognitive function correlated to EQ but not to CCS. Perceived physical function/general health explained 9% of HRQL and was as expected related both to EQ and CCS. Total CHP scores differed significantly to those of healthy controls. CONCLUSIONS: Perceived cognitive function seems to be a major determinant of HRQL in CAD patients. This, in addition to earlier reports of possible prognostic information of reduced cognitive function, would prompt us to propose that HRQL assessments should include questions aimed to assess cognitive function.

Aged↗

PubMed2003

A novel family of tRNA-derived SINEs in the colugo and two new retrotransposable markers separating dermopterans from primates.

Short interspersed nuclear elements (SINEs) provide a near homoplasy free and copious source of molecular evolutionary markers with precisely defined character polarity. Used as molecular cladistic markers in presence/absence analyses, they represent a powerful complement to phylogenetic reconstructions that are based on sequence comparisons on the level of nucleotide substitutions. Recent sequence comparisons of large data sets incorporating a broad eutherian taxonomic sample have led to considerations of the different primate infraorders to constitute a paraphyletic group. Statistically significant support against the monophyly of primates has been obtained by clustering the flying lemur-also termed colugo-(Cynocephalus, Dermoptera) amidst the primates as the sister group to anthropoid primates (New World monkeys, Old World monkeys, and hominoids). We discovered retrotransposed markers that clearly favor the monophyly of primates, with the markers specific to all extant primates but definitively absent at the orthologous loci in the flying lemur and other non-primates. By screening the colugo genome for phylogenetic informative SINEs, we also recovered a novel family of dermopteran specific SINE elements that we call CYN. This element is probably derived from the isoleucine tRNA and appears in monomeric, dimeric, and trimeric forms. It has no long tRNA unrelated region and no poly(A) linker between the monomeric subunits. The characteristics of the novel CYN-SINE family indicate a relatively recent history. Therefore, this SINE family is not suitable to solve the phylogenetic affiliation between dermopterans and primates. Nevertheless it is a valuable device to reconstruct the evolutionary steps from a functional tRNA to an interspersed SINE element.

Animals↗

PubMed2002

Mammalian sperm proteins are rapidly evolving: evidence of positive selection in functionally diverse genes.

A growing number of genes involved in sex and reproduction have been demonstrated to be rapidly evolving. Here, we show that genes expressed solely in spermatozoa represent a highly diverged subset among mouse and human tissue-specific orthologs. The average rate of nonsynonymous substitutions per site (K(a)) is significantly higher in sperm proteins (mean K(a) = 0.18; N = 35) than in proteins expressed specifically in all other tissues (mean K(a) = 0.074; N = 473). No differences, however, are found in the synonymous substitution rate (K(s)) between tissues, suggesting that selective forces, and not mutation rate, explain the high rate of replacement substitutions in sperm proteins. Four out of 19 sperm-specific genes with characterized function demonstrated evidence of strong positive Darwinian selection, including a protein involved in gene regulation, Protamine-1 (PRM1), a protein involved in glycolysis, GAPDS, and two egg-binding proteins, Adam-2 precursor (ADAM2) and sperm-adhesion molecule-1 (SAM1). These results demonstrate the rapid evolution of sperm-specific genes and highlight the molecular action of sexual selection on a variety of characters involved in mammalian sperm function.

Amino Acid Substitution↗

PubMed2006

Development of a clinical prediction rule for classifying patients with patellofemoral pain syndrome who respond to patellar taping.

STUDY DESIGN: Predictive validity/diagnostic test study. OBJECTIVE: To determine the predictive validity and interrater reliability of selected clinical exam items and to develop a clinical prediction rule (CPR) to determine which patients respond successfully to patellar taping. BACKGROUND: Patellar taping is often used to treat patients with PFPS. However, the characteristics of the patients who respond best to patellar taping intervention have not been identified. METHODS AND MEASURES: Fifty volunteers (27 males, 23 females) with PFPS underwent a standardized clinical examination. Diagnosis of PFPS was based on the complaint of retropatellar pain that was provoked by a partial squat or stair ascent/descent. Subjects performed 3 functional activities and rated their pain during each activity on a numerical rating scale (NPRS). All subjects received treatment with a medial glide patellar-taping technique and repeated the functional activities and pain ratings. An immediate 50% reduction in pain or moderate improvement on a global rating of change (GRC) questionnaire was considered a treatment success. Likelihood ratios (LRs) were calculated to determine which examination items were most predictive of treatment outcome. Logistic regression analysis identified items included in the CPR. RESULTS: Twenty-six subjects (52%) had an immediate successful response to the intervention. Two examination items (positive patellar tilt test or tibial varum greater than 5 degrees, +LR = 4.4) comprised the CPR. Application of the CPR improved the probability of a successful outcome from 52% to 83%. Fifty-eight percent of the lower extremity measures were associated with moderate to good reliability (reliability coefficient range, 0.52-0.84). The reliability coefficients for the items that comprised the CPR were 0.49 (patellar tilt) and 0.66 (tibial varum). CONCLUSION: A CPR was developed to predict an immediate successful response to a medial glide patellar taping technique. Validation of the CPR in an independent sample is necessary before widespread clinical use can be recommended.

Adolescent↗

PubMed1999

Statistical methods for mapping quantitative trait loci from a dense set of markers.

Lander and Botstein introduced statistical methods for searching an entire genome for quantitative trait loci (QTL) in experimental organisms, with emphasis on a backcross design and QTL having only additive effects. We extend their results to intercross and other designs, and we compare the power of the resulting test as a function of the magnitude of the additive and dominance effects, the sample size and intermarker distances. We also compare three methods for constructing confidence regions for a QTL: likelihood regions, Bayesian credible sets, and support regions. We show that with an appropriate evaluation of the coverage probability a support region is approximately a confidence region, and we provide a theroretical explanation of the empirical observation that the size of the support region is proportional to the sample size, not the square root of the sample size, as one might expect from standard statistical theory.

Chromosome Mapping↗

PubMed1996

Detection of brain activation signal from functional magnetic resonance imaging data.

An image-processing strategy for functional magnetic resonance imaging (fMRI) data sets consisting of sequential images of the same slice of brain tissue is considered. An algorithm of detection based on the likelihood-ratio test and the noise properties in fMRI is introduced. Since the data have a poor signal-to-noise ratio, and in order to make detection reliable, the algorithm is organized in two steps: (1) pixel detection, which detects all pixels having significant changes, thus building regions of interest (ROIs), and (2) region detection, which selects the most likely activated region from obtained ROIs. The detection method is applied to experimental fMRI data from the motor cortex and compared with the cross-correlation method and Student's t test commonly applied by others. The results obtained using the likelihood-ratio test show improvement in the detection of activated regions.

Algorithms↗

PubMed2000

A new approach to adjust for multivariate confounders in small randomized studies applied to dendritic cell vaccination data.

In small studies, randomization alone is unlikely to eliminate confounding. In linear models, confounding can be addressed by including additional dependent variables, adding covariates, or stratifying the data for the analysis. When the functional relation between observed variables and underlying (latent) factors is unknown, however, methods based on ranks may be more appropriate than ANOVA. It is demonstrated, how the marginal likelihood principle can be used to provide objective and intrinsically valid procedures to adjust for (multiple) confounders when the assumptions of the linear model cannot be justified.

Cancer Vaccines↗