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Results for “Likelihood Functions”

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PubMed2005

Emergence of young human genes after a burst of retroposition in primates.

The origin of new genes through gene duplication is fundamental to the evolution of lineage- or species-specific phenotypic traits. In this report, we estimate the number of functional retrogenes on the lineage leading to humans generated by the high rate of retroposition (retroduplication) in primates. Extensive comparative sequencing and expression studies coupled with evolutionary analyses and simulations suggest that a significant proportion of recent retrocopies represent bona fide human genes. We estimate that at least one new retrogene per million years emerged on the human lineage during the past approximately 63 million years of primate evolution. Detailed analysis of a subset of the data shows that the majority of retrogenes are specifically expressed in testis, whereas their parental genes show broad expression patterns. Consistently, most retrogenes evolved functional roles in spermatogenesis. Proteins encoded by X chromosome-derived retrogenes were strongly preserved by purifying selection following the duplication event, supporting the view that they may act as functional autosomal substitutes during X-inactivation of late spermatogenesis genes. Also, some retrogenes acquired a new or more adapted function driven by positive selection. We conclude that retroduplication significantly contributed to the formation of recent human genes and that most new retrogenes were progressively recruited during primate evolution by natural and/or sexual selection to enhance male germline function.

Animals↗

PubMed1996

Confidence intervals for median survival times under a piecewise exponential model with proportional hazards covariate effects.

Brookmeyer and Crowley derived a non-parametric confidence interval for the median survival time of a homogeneous population by inverting a generalization of the sign test for censored data. The 1-alpha confidence interval for the median is essentially the set of all values t such that the Kaplan--Meier estimate of the survival function at time t does not differ significantly from one-half at significance level alpha. Here I extend the method to incorporate covariates into the analysis by assuming an underlying piecewise exponential model with proportional hazards covariate effects. Maximum likelihood estimates of the model parameters are obtained via iterative techniques, from which the estimated (log) survival curve is easily constructed. The delta method provides asymptotic standard errors. Following Brookmeyer and Crowley, I find the confidence interval for the median survival time at a specified value of the covariate vector by inverting the sign test. I illustrate the methods using data from a clinical trial conducted by the Radiation Therapy Oncology Group in cancer of the mouth and throat. It is seen that the piecewise exponential model provides considerable flexibility in accommodating to the shape of the underlying survival curve and thus offers advantages to other, more restrictive, parametric models. Simulation studies indicate that the method provides reasonably accurate coverage probabilities.

Age Factors↗

PubMed2006

Is N-terminal pro B-type natriuretic peptide (NT-proBNP) a useful screening test for angiographic findings in patients with stable coronary disease?

BACKGROUND: Whether N-terminal pro B-type natriuretic peptide (NT-proBNP) is a useful screening tool for angiographic coronary artery disease in patients with angina is not known. Therefore, the purpose of this study was to assess the diagnostic test performance of NT-proBNP in detecting coronary atherosclerotic lesions, as assessed by coronary angiography. METHODS: We examined 1034 patients referred for diagnostic angiography because of symptoms or signs of coronary artery disease. The diagnostic value of NT-proBNP in predicting clinically significant coronary disease was assessed. RESULTS: In a multiple logistic regression model, NT-proBNP above the upper normal limit (125 pg/mL) predicted clinically significant coronary disease at angiography independently of traditional cardiovascular risk factors and invasive measurements of left ventricular function (odds ratio 2.1, 95% CI 1.3-3.2, P = .001). The ability of NT-proBNP in detecting clinically significant coronary disease at angiography was modest, however, with sensitivity of 0.61, specificity 0.60, accuracy 61 (95% CI 58-64), positive likelihood ratio 1.5 (95% CI 1.3-1.8), negative likelihood ratio 0.7 (95% CI 0.6-0.8), and area under the ROC curve 0.61 (95% CI 0.58-0.64). CONCLUSIONS: NT-proBNP is associated with clinically significant coronary disease at angiography, independently of left ventricular dysfunction. However, NT-proBNP is not a useful screening test for diagnosing significant angiographic lesions in patients with stable coronary disease.

Angina Pectoris↗

PubMed2005

Estimating age change in list recall in asset and health dynamics of the oldest-old: the effects of attrition bias and missing data treatment.

Average change in list recall was evaluated as a function of missing data treatment (Study 1) and dropout status (Study 2) over ages 70 to 105 in Asset and Health Dynamics of the Oldest-Old data. In Study 1 the authors compared results of full-information maximum likelihood (FIML) and the multiple imputation (MI) missing-data treatments with and without independent predictors of missingness. Results showed declines in all treatments, but declines were larger for FIML and MI treatments when predictors were included in the treatment of missing data, indicating that attrition bias was reduced. In Study 2, models that included dropout status had better fits and reduced random variance compared with models without dropout status. The authors conclude that change estimates are most accurate when independent predictors of missingness are included in the treatment of missing data with either MI or FIML and when dropout effects are modeled.

Aged↗

PubMed2004

[Dynamic contour tracking of medical images based on improved particle filter].

In the research of medical image processing, motion estimation and tracking relating to the region of interest has been given considerable attention. For improving the quality of the noisy or cluttered medical images, the particle filter (PF) based on the non-linear and non-Gaussian Bayesian State Estimation is a better as well as a technically challenging solution. As the algorithm of particle weights, especially the importance density function, often severely affects the performance of the PF, we propose in this paper a better algorithm for its improvement; in addition, to ensure better tracking of the dynamic contour with the PF, we proposed a new algorithm for the likelihood and prior probability density. Objective theoretical evaluation and substantial comparative experiments suggest that this method can be a good solution for accurate dynamic contour tracking.

Algorithms↗

PubMed1997

Multi-level models for longitudinal growth norms.

Multi-level models for estimating conditional and unconditional longitudinal growth norms are presented. The procedure involves transforming the original growth measurements to Normality and modelling these with a two-level random coefficient model. Growth norms for any desired time interval and function can be derived. Height and weight data are used for illustration.

Adolescent↗

PubMed2001

Accelerated molecular evolution of insect orthologues of ERG28/C14orf1: a link with ecdysteroid metabolism?

We have analysed the evolution of ERG28/C14orf1, a gene coding for a protein involved in sterol biosynthesis. While primary sequence of the protein is well conserved in all organisms able to synthesize sterols de novo, strong divergence is noticed in insects, which are cholesterol auxotrophs. In spite of this virtual acceleration, our analysis suggests that the insect orthologues are evolving today at rates similar to those of the remaining members of the family. A plausible way to explain this acceleration and subsequent stabilization is that Erg28 plays a role in at least two different pathways. Discontinuation of the cholesterogenesis pathway in insects allowed the protein to evolve as much as the function in the other pathway was not compromised.

Animals↗

PubMed2004

Adaptive evolution of scorpion sodium channel toxins.

Gene duplication followed by positive Darwinian selection is an important evolutionary event at the molecular level, by which a gene can gain new functions. Such an event might have occurred in the evolution of scorpion sodium channel toxin genes (alpha- and beta-groups). To test this hypothesis, a robust statistical method from Yang and co-workers based on the estimation of the nonsynonymous-to-synonymous rate ratio (omega = d(N)/ d(S)) was performed. The results provide clear statistical evidence for adaptive molecular evolution of scorpion alpha- and beta-toxin genes. A good match between the positively selected sites (evolutionary epitopes) and the putative bioactive surface (functional epitopes) indicates that these sites are most likely involved in functional recognition of sodium channels. Our results also shed light on the importance of the B-loop in the functional diversification of scorpion alpha- and beta-toxins.

Adaptation, Physiological↗

PubMed2006

Loss of function polymorphisms in NAT1 protect against spina bifida.

Periconceptional folic acid supplementation reduces the risk of having a child with spina bifida. N-acetyltransferase 1 (NAT1) participates in the catabolism of folates and the acetylation of aromatic and heterocyclic amines. Hence, functional polymorphisms in NAT1, the gene encoding NAT1, could influence the risk of spina bifida via either folate catabolism or acetylation of exogenous agents. Individuals with spina bifida and their parents were genotyped for six NAT1 single nucleotide polymorphisms (SNPs) for which the less common allele is associated with reduced or absent enzyme activity (i.e. 97C>T, 190C>T, 559C>T/560G>A, 640T>G and 752A>T). In addition, a "composite" NAT1 genotype was defined as a function of the genotyped SNPs. Descriptive analyses of the SNPs and of the composite genotype indicated that heterozygous parents were more likely to transmit the common allele than the rare allele to their affected offspring. Furthermore, matings of mothers homozygous for the common allele and heterozygous fathers were more common than the reciprocal matings. Log-linear analyses confirmed that both the maternal (P = 0.008) and offspring (P = 0.003) composite NAT1 genotypes were significantly related to the risk of spina bifida. NAT1 variants that reduce or abolish enzyme activity appear to protect against spina bifida, and to exert their influence via both the maternal and the offspring genotypes. These associations may be attributable to a decrease in either folate catabolism or the conversion of exogenous agents to teratogenic derivatives in women and/or developing embryos with a NAT1 genotype that includes a loss of function allele relative to those who do not.

Adult↗

PubMed1986

Plicatic acid-specific IgE and nonspecific bronchial hyperresponsiveness in western red-cedar workers.

In a cross-sectional survey of 652 workers in a western red-cedar sawmill, we obtained data on symptoms, pulmonary function, immediate skin reactivity to common allergens, nonspecific bronchial responsiveness, total IgE level, and sensitization to plicatic acid conjugated with human serum albumin as measured by RAST. Dust exposure was estimated by personal and area sampling for total dust during a work shift and cumulative exposure by duration of employment. Seven percent of the workers had an elevated RAST, and 20% had nonspecific bronchial hyperresponsiveness. Elevation in RAST was associated with bronchial hyperresponsiveness. Almost half (46%) of the workers with RAST elevation had bronchial hyperresponsiveness compared to 18% in workers with no RAST elevation. The association was unaffected by total IgE level or by limiting the analysis to workers without respiratory symptoms and was most apparent in younger workers. Bronchial hyperresponsiveness was associated with increased prevalence of respiratory symptoms as well as with lower levels of pulmonary function. The likelihood of bronchial hyperresponsiveness increased with increasing age but was unrelated to the dust-exposure concentration. RAST elevation was unrelated to employment duration or dust exposure and was not associated with an increased prevalence of symptoms or lower levels of pulmonary function independent of bronchial hyperresponsiveness. We conclude that plicatic acid-specific IgE and nonspecific bronchial hyperresponsiveness are associated in western red-cedar workers and that this association may reflect a causal connection.

Adult↗

PubMed1998

A comparison between TNM and TANIS stage grouping for predicting prognosis of oral and oropharyngeal cancer.

PURPOSE: The 1987 TNM classification system modified some T and N definition but it did not change stage grouping. Consequently it has not improved the prognostic validity of the advanced stage groups. In 1993, a new stage grouping was purposed, TANIS, that seems to have a higher correlation with survival. In this report, the TNM classification and TANIS system were compared to evaluate this prognostic ability. PATIENTS AND METHODS: Data from 164 patients affected by primary cancers of oropharynx or oral cavity were analyzed by means of Kaplan-Meier and Cox regression analysis. RESULTS: The crude survival rate at 5 years was 43.9%. Both systems showed a significant correlation with the survival rate by means of Cox regression analysis. TANIS subcategories were correlated to the mortality rate in the stage IV patients. TANIS resulted a better predictor of mortality when compared with TNM. CONCLUSION: The TANIS system was able to separate the TNM stage IV patients into prognostic groups, yielding more information with respect to TNM for such a category of patients. When a comparison between TNM and TANIS was performed, it was observed that TANIS had a higher correlation with survival rate, whereas TNM did not add any information in defining the survival function.

Adult↗

PubMed2000

Statistics of transmitter release at nerve terminals.

This review presents an historical account of the developments of the statistical analysis of quantal transmission over the past half century and of the progress made in using this approach to reveal new properties of nerve terminals. In the early 1950s, Katz and his colleagues showed that evoked transmitter release occurred in quanta at the neuromuscular junction, opening up the study of transmitter release at nerve terminals to statistical analysis. In the subsequent two decades attempts were made to see if evoked quantal release could be described by binomial or compound binomial statistics, as originally suggested by Katz, and to relate the parameters of the statistic to various structures of the nerve terminal. During this period two hypotheses were enunciated, namely the 'vesicle hypothesis', which states that quanta arise as a consequence of the packaging of transmitter in vesicles; and the 'active zone hypothesis', which states that vesicles undergo exocytosis at discrete sites on the nerve terminal. Unsuccessful attempts were made to relate the binomial parameter n to the elements in these hypotheses, that is to the number of active zones possessed by the terminal or the number of vesicles available for release at these zones. This difficulty was part resolved in the late 1970s with the application of non-uniform binomial statistics to transmitter release from nerve terminals, in which n is the number of active zones each with their individual probabilities, p(j). Autocorrelation functions were subsequently introduced to detect if transmitter release is quantised at a particular nerve terminal. Statistical methods which would allow discrimination between different models of transmitter release over the active zones of a terminal were then developed. The introduction of maximum likelihood estimation procedures then allowed estimates to be made of the parameters in the statistical models of quantal release. The application of these procedures to experimental data from a variety of nerve terminals provided evidence for the concept that each synapse, taken as possessing a single active zone, possesses its own individual probability of secretion of a quantum by the exocytosis of a vesicle. In the late 1960s Stevens introduced the first stochastic approach to the analysis of the kinetics of the release of a quantum of transmitter at the neuromuscular junction following an impulse. In the subsequent decades this was developed into an explicit theory for the interaction of proteins involved in regulated exocytosis of a vesicle at an active zone. The parameters were the number of transition steps in the release process (k), each occurring at the same rate (alpha), with the possibility of each of these steps becoming blocked at the same rate (gamma). Maximum likelihood estimation procedures could then be used to obtain these parameter values. The discovery was made in the 1990s of the core proteins of the SNARE complex that govern regulated exocytosis. This offers the possibility in the near future of identifying the kinetic interaction of these proteins with the parameters of the stochastic process of exocytosis which confer a particular probability on individual synapses.

Animals↗

PubMed2003

A codon-based model of host-specific selection in parasites, with an application to the influenza A virus.

Parasites sometimes expand their host range by acquiring a new host species. After a host change event, the selective regime acting on a given parasite gene may change as a result of host-specific adaptive alterations of protein functionality or host-specific immune-mediated selection. We present a codon-based model that attempts to include these effects by allowing the position-specific substitution process to change in conjunction with a host change event. Following maximum-likelihood parameter estimation, we employ an empirical Bayesian procedure to identify candidate sites potentially involved in host-specific adaptation. We discuss the applicability of the model to the more general problem of ascertaining whether the selective regime differs in two groups of related organisms. The utility of the model is illustrated on a data set of nucleoprotein sequences from the influenza A virus obtained from avian and human hosts.

Animals↗

PubMed2005

Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi.

BACKGROUND: The trypanosomatids Leishmania major, Trypanosoma brucei and Trypanosoma cruzi cause some of the most debilitating diseases of humankind: cutaneous leishmaniasis, African sleeping sickness, and Chagas disease. These protozoa possess complex life cycles that involve development in mammalian and insect hosts, and a tightly coordinated cell cycle ensures propagation of the highly polarized cells. However, the ways in which the parasites respond to their environment and coordinate intracellular processes are poorly understood. As a part of an effort to understand parasite signaling functions, we report the results of a genome-wide analysis of protein kinases (PKs) of these three trypanosomatids. RESULTS: Bioinformatic searches of the trypanosomatid genomes for eukaryotic PKs (ePKs) and atypical PKs (aPKs) revealed a total of 176 PKs in T. brucei, 190 in T. cruzi and 199 in L. major, most of which are orthologous across the three species. This is approximately 30% of the number in the human host and double that of the malaria parasite, Plasmodium falciparum. The representation of various groups of ePKs differs significantly as compared to humans: trypanosomatids lack receptor-linked tyrosine and tyrosine kinase-like kinases, although they do possess dual-specificity kinases. A relative expansion of the CMGC, STE and NEK groups has occurred. A large number of unique ePKs show no strong affinity to any known group. The trypanosomatids possess few ePKs with predicted transmembrane domains, suggesting that receptor ePKs are rare. Accessory Pfam domains, which are frequently present in human ePKs, are uncommon in trypanosomatid ePKs. CONCLUSION: Trypanosomatids possess a large set of PKs, comprising approximately 2% of each genome, suggesting a key role for phosphorylation in parasite biology. Whilst it was possible to place most of the trypanosomatid ePKs into the seven established groups using bioinformatic analyses, it has not been possible to ascribe function based solely on sequence similarity. Hence the connection of stimuli to protein phosphorylation networks remains enigmatic. The presence of numerous PKs with significant sequence similarity to known drug targets, as well as a large number of unusual kinases that might represent novel targets, strongly argue for functional analysis of these molecules.

Animals↗

PubMed1993

Repeated measurement designs with random selections.

We consider repeated measurement designs with a single group as well as with multiple groups. Conventionally, the repeated measurements are made at fixed, often evenly spaced times. The first and second moment conditions needed for an exact F test are not satisfied in general, but with random permutation of the times, a probability measure results that does satisfy these moment conditions, unconditionally. As a consequence, unfortunately, we lose the asymptotic normality that is also essential to justify an F test. We introduce a class of designs and estimators for which both the moment conditions and asymptotic normality are satisfied. The times are the same for all subjects and they are chosen in such a way that they are mutually independent and identically distributed. It is important to understand that our conditions are satisfied only unconditionally--that is, if we do not condition by the randomly chosen times. There is a small probability that the randomly sampled times could be very unevenly allocated. Since we are not conditioning by the times, strictly speaking, this does not matter. It is possible to impose a mild condition of "spread," as we show, at small cost in terms of the P-value. Our method of design makes it possible to do regression analysis, interval estimation, and hypothesis testing on the mean response as a function of time. Because we have mutual independence and identical distributions of times we can form confidence bands.

Animals↗

PubMed1976

Prognosis for recovery of function in acute renal failure. Value of the renal image obtained using iodohippurate sodium I 131.

Twenty-four survivors of acute, nonobstructive, nonnephritic renal failure had a renal scan using iodohippurate sodium I 131 performed early in the acute illness. Scans were judged according to whether the renal images were prominent, faint, or absent during the first 30 minutes after intravenous injection of 100 to 250 microcuries of iodohippurate sodium I 131. All ten patients with prominent renal images attained life-sustaining renal function with an average postrecovery creatinine clearance of 80 ml/min. Of the seven patients with faint renal images, six recovered life-sustaining renal function (average creatinine clearance of 39 ml/min), and one required chronic hemodialysis. Seven patients had no renal image initially; four recovered life-sustaining renal function with an average creatinine clearance of 25 ml/min; three required chronic hemodialysis. We conclude that, for patients with acute renal failure, the appearance of the renal image obtained using this substance is an important indicator of renal viability and of the likelihood for functional recovery.

Acute Kidney Injury↗

PubMed2000

Molecular evolution of cytochrome c oxidase subunit I in primates: is there coevolution between mitochondrial and nuclear genomes?

Phylogenetic analyses carried out on cytochrome c oxidase (COX) subunit I mitochondrial genes from 14 primates representing the major branches of the order and four outgroup nonprimate eutherians revealed that transversions and amino acid replacements (i.e., the more slowly occurring sequence changes) contained lower levels of homoplasy and thus provided more accurate information on cladistic relationships than transitions (i.e., the more rapidly occurring sequence changes). Several amino acids, each with a high likelihood of functionality involving the binding of cytochrome c or interaction with COX VIII, have changed in Anthropoidea, the primate suborder grouping New World monkey, Old World monkey, ape, and human lineages. They are conserved in other mammalian lineages and in nonanthropoid primates. Maximum-likelihood ancestral COX I nucleotide sequences were determined utilizing a near most parsimonious branching arrangement for the primate sequences that was consistent with previously hypothesized primate cladistic relationships based on larger and more diverse data sets. Relative rate tests of COX I mitochondrial sequences showed an elevated nonsynonymous (N) substitution rate for anthropoid-nonanthropoid comparisons. This finding for the largest mitochondrial (mt) DNA-encoded subunit is consistent with previous observations of elevated nonsynonymous substitution/synonymous substitution (S) rates in primates for mt-encoded COX II and for the nuclear-encoded COX IV and COX VIIa-H. Other COX-related proteins, including cytochrome c and cytochrome b, also show elevated amino acid replacement rates or N/S during similar time frames, suggesting that this group of interacting genes is likely to have coevolved during primate evolution.

Amino Acid Sequence↗

PubMed2001

Slope bias of psychometric functions derived from adaptive data.

Several investigators have fit psychometric functions to data from adaptive procedures for threshold estimation. Although the threshold estimates are in general quite correct, one encounters a slope bias that has not been explained up to now. The present paper demonstrates slope bias for parametric and nonparametric maximum-likelihood fits and for Spearman-Kärber analysis of adaptive data. The examples include staircase and stochastic approximation procedures. The paper then presents an explanation of slope bias based on serial data dependency in adaptive procedures. Data dependency is first illustrated with simple two-trial examples and then extended to realistic adaptive procedures. Finally, the paper presents an adaptive staircase procedure designed to measure threshold and slope directly. In contrast to classical adaptive threshold-only procedures, this procedure varies both a threshold and a spread parameter in response to double trials.

Algorithms↗