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PubMed2005

HEGESMA: genome search meta-analysis and heterogeneity testing.

SUMMARY: Heterogeneity and genome search meta-analysis (HEGESMA) is a comprehensive software for performing genome scan meta-analysis, a quantitative method to identify genetic regions (bins) with consistently increased linkage score across multiple genome scans, and for testing the heterogeneity of the results of each bin across scans. The program provides as an output the average of ranks and three heterogeneity statistics, as well as corresponding significance levels. Statistical inferences are based on Monte Carlo permutation tests. The program allows both unweighted and weighted analysis, with the weights for each study as specified by the user. Furthermore, the program performs heterogeneity analyses restricted to the bins with similar average ranks. AVAILABILITY: http://biomath.med.uth.gr.

Chromosome Mapping↗
PubMed2001

Projections of lung cancer mortality in West Germany: a case study in Bayesian prediction.

We apply a generalized Bayesian age-period-cohort (APC) model to a data-set on lung cancer mortality in West Germany, in the period 1952-1996. Our goal is to predict future death rates until the year 2010, separately for males and females. Since age and period are not measured on the same grid, we propose a generalized APC model where consecutive cohort parameters represent strongly overlapping birth cohorts. This approach results in a rather large number of parameters, where standard algorithms for statistical inference by Markov chain Monte Carlo methods turn out to be computationally intensive. We propose a more efficient implementation based on ideas of block sampling from the time series literature. We entertain two different formulations, penalizing either first or second differences of age, period and cohort parameters. To assess the predictive quality of both formulations, we first forecast the rates for the period 1987-1996 based on data until 1986. A comparison with the actual observed rates is made based on a predictive deviance criterion. Predictions of lung cancer mortality until 2010 are then reported and a modification of the formulation in order to include information on cigarette consumption is finally described.To whom correspondence should be addressed. Currently at Imperial College School of Medicine, Department of Epidemiology and Public Health, Norfolk Place, London W2 1PG, UK.

Journal Article↗
PubMed2003

The spherical deformation model.

Miller et al. (1994) describe a model for representing spatial objects with no obvious landmarks. Each object is represented by a global translation and a normal deformation of a sphere. The normal deformation is defined via the orthonormal spherical-harmonic basis. In this paper we analyse the spherical deformation model in detail and describe how it may be used to summarize the shape of star-shaped three-dimensional objects with few parameters. It is of interest to make statistical inference about the three-dimensional shape parameters from continuous observations of the surface and from a single central section of the object. We use maximum-likelihood-based inference for this purpose and demonstrate the suggested methods on real data.

Analysis of Variance↗
PubMed2004

Maximum likelihood estimation of ordered multinomial parameters.

The pool adjacent violator algorithm Ayer et al. (1955, The Annals of Mathematical Statistics, 26, 641-647) has long been known to give the maximum likelihood estimator of a series of ordered binomial parameters, based on an independent observation from each distribution (see Barlow et al., 1972, Statistical Inference under Order Restrictions, Wiley, New York). This result has immediate application to estimation of a survival distribution based on current survival status at a set of monitoring times. This paper considers an extended problem of maximum likelihood estimation of a series of 'ordered' multinomial parameters p(i)= (p(1i),p(2i),.,p(mi)) for 1 <or=i <ro=k, where ordered means that p(j1) <or=p(j2) <or=<or=p(jk) for each j with 1 <or=j <or=m-1. The data consist of k independent observations X(1),., X(k) where X(i) has a multinomial distribution with probability parameter p(i) and known index n(i)\geq 1. By making use of variants of the pool adjacent violator algorithm, we obtain a simple algorithm to compute the maximum likelihood estimator of p(1),., p(k), and demonstrate its convergence. The results are applied to nonparametric maximum likelihood estimation of the sub-distribution functions associated with a survival time random variable with competing risks when only current status data are available (Jewell et al. 2003, Biometrika, 90, 183-197).

Age Factors↗
PubMed2000

A mixed-model approach to mapping quantitative trait loci in barley on the basis of multiple environment data.

In this article, I propose a mixed-model method to detect QTL with significant mean effect across environments and to characterize the stability of effects across multiple environments. I demonstrate the method using the barley dataset by the North American Barley Genome Mapping Project. The analysis raises the need for mixed modeling in two different ways. First, it is reasonable to regard environments as a random sample from a population of target environments. Thus, environmental main effects and QTL-by-environment interaction effects are regarded as random. Second, I expect a genetic correlation among pairs of environments caused by undetected QTL. I show how random QTL-by-environment effects as well as genetic correlations are straightforwardly handled in a mixed-model framework. The main advantage of this method is the ability to assess the stability of QTL effects. Moreover, the method allows valid statistical inferences regarding average QTL effects.

Crosses, Genetic↗
PubMed2002

Estimating mutation parameters, population history and genealogy simultaneously from temporally spaced sequence data.

Molecular sequences obtained at different sampling times from populations of rapidly evolving pathogens and from ancient subfossil and fossil sources are increasingly available with modern sequencing technology. Here, we present a Bayesian statistical inference approach to the joint estimation of mutation rate and population size that incorporates the uncertainty in the genealogy of such temporally spaced sequences by using Markov chain Monte Carlo (MCMC) integration. The Kingman coalescent model is used to describe the time structure of the ancestral tree. We recover information about the unknown true ancestral coalescent tree, population size, and the overall mutation rate from temporally spaced data, that is, from nucleotide sequences gathered at different times, from different individuals, in an evolving haploid population. We briefly discuss the methodological implications and show what can be inferred, in various practically relevant states of prior knowledge. We develop extensions for exponentially growing population size and joint estimation of substitution model parameters. We illustrate some of the important features of this approach on a genealogy of HIV-1 envelope (env) partial sequences.

Decision Trees↗
PubMed1974

A model for analysis of population structure.

Arguments have been presented for the appropriateness of a multinomial Dirichlet distribution for describing single-locus genotypic frequencies in a subdivided population. This distribution is defined as a function of allele frequency, the average (over the entire population) inbreeding coefficient and the correlation between genotypes within a subdivision. Alternative parameterizations and their genetic interpretations are given.-We then show how information from a sample drawn from this subdivided population, in the absence of pedigrees, can be combined with the multinomial Dirichlet model to form a likelihood function. This likelihood function is then used as the basis for estimation and testing hypotheses concerning the genetic parameters of the model. Comparisons of this approach to the alternative procedure of Cockerham (1969) and (1973) are made using human data obtained from Tecumseh, Michigan and Monte Carlo simulations.-Finally, implications of these results to statistical inference and to mutation rates are presented.

Alleles↗
PubMed1985

Trends in childhood tuberculosis in Hungary 1953-1983: quantitative methods for evaluation of BCG policy.

To analyse the effectiveness of the BCG policy on childhood tuberculosis in Hungary, the following three quantitative methods have been organized and systematically applied since 1959; regression analysis with multiple comparison of the incidence trends of age groups; stepwise regression analysis to select the strongest childhood incidence decrease factor; and a log-linear model to compare the risk of disease in vaccinated and non-vaccinated children. The increasing BCG coverage of children as a specific antituberculous measure (i) has decreased the childhood incidence (23-32% per year) 3-4 times more rapidly than the adult incidence (6-16% per year) as shown by the regression analysis, (ii) has acted as the strongest incidence decrease effect among other factors and (iii) has protected the vaccinated children 2.8 times better than the non-vaccinated ones. The use of valid and exact models, from statistical inferences ensure the objective interpretation of the epidemiological events in tuberculosis.

Adolescent↗
PubMed1990

Multivariate refutation of aetiological hypotheses in non-experimental epidemiology.

Extension of Karl Popper's logic of refutation from the realm of contingency tables to multivariate modelling leads to the conclusion that rigorously scientific multivariate analysis in non-experimental epidemiology differs from the traditional quasi-scientific approach. Instead of aiming for high sensitivity in detecting aetiological agents, the goal in refutation is high specificity--to give the best defence of the 'innocence' of every exposure hypothesized as being a cause. Instead of 'forward selection' or 'backward elimination', multivariate refutation uses the method of 'forward elimination'. This entails a likelihood approach (which may be complemented by, but should be demarcated from, Bayesian methods) not only for statistical inference but also, by analogy, for study design and conduct: one starts with the conclusion (the estimate or hypothesis) and works backwards to the observations (the likelihood of the data or the design of the study). Differences in practice can sometimes be large, as illustrated by a study of hypothesized triggers of myocardial infarction. Multivariate refutation should replace the concept of multivariate modelling in non-experimental epidemiology.

Bayes Theorem↗
PubMed1988

Regression models in clinical studies: determining relationships between predictors and response.

Multiple regression models are increasingly being applied to clinical studies. Such models are powerful analytic tools that yield valid statistical inferences and make reliable predictions if various assumptions are satisfied. Two types of assumptions made by regression models concern the distribution of the response variable and the nature or shape of the relationship between the predictors and the response. This paper addresses the latter assumption by applying a direct and flexible approach, cubic spline functions, to two widely used models: the logistic regression model for binary responses and the Cox proportional hazards regression model for survival time data.

Humans↗
PubMed2005

Site-to-site variation of synonymous substitution rates.

We develop a new model for studying the molecular evolution of protein-coding DNA sequences. In contrast to existing models, we incorporate the potential for site-to-site heterogeneity of both synonymous and nonsynonymous substitution rates. We demonstrate that within-gene heterogeneity of synonymous substitution rates appears to be common. Using the new family of models, we investigate the utility of a variety of new statistical inference procedures, and we pay particular attention to issues surrounding the detection of sites undergoing positive selection. We discuss how failure to model synonymous rate variation in the model can lead to misidentification of sites as positively selected.

Amino Acid Substitution↗
PubMed1988

Illness and reservoirs associated with Giardia lamblia infection in rural Egypt: the case against treatment in developing world environments of high endemicity.

A longitudinal investigation of the health effects and reservoirs of Giardia was undertaken during 1984-1985 in 40 households located in the rural Nile Delta region of Egypt. Stool specimens obtained once weekly for six months from 2-4-year-old children were cyst- or trophozoite-positive in 42% of the 724 examined. Only one child remained Giardia-negative during the study. The mean duration of excretion in Giardia-positive children was seven and one-half weeks with a range of one to 17 weeks. Mucus was present in 52% of all stools collected, and fecal leukocytes were observed with surprising frequency in the absence of identifiable pathogens. Clinical symptoms of illness were frequently observed within a month before or after Giardia excretion in stool of children, but a statistical inference of association was not demonstrated. Seventeen per cent of 697 specimens obtained from their mothers were Giardia-positive for a mean duration of four weeks and a range of one to 18 weeks. A total of 962 specimens were collected from 13 species of household livestock. Giardia was detected in 22 specimens from cows, goats, sheep, and one duck. Giardia cysts were detected in three of 899 samples of household drinking water. The ubiquity of the protozoan as well as the failure to show an association between infection and symptomatic illness argue against the administration of Giardia-specific drugs to children in settings where the risk of reinfection is high and for whom intestinal insults are both varied and constant.

Animals↗
PubMed1996

Relative apparent synapomorphy analysis (RASA). I: The statistical measurement of phylogenetic signal.

We have developed a new approach to the measurement of phylogenetic signal in character state matrices called relative apparent synapomorphy analysis (RASA). RASA provides a deterministic, statistical measure of natural cladistic hierarchy (phylogenetic signal) in character state matrices. The method works by determining whether a measure of the rate of increase of cladistic similarity among pairs of taxa as a function of phenetic similarity is greater than a null equiprobable rate of increase. Our investigation of the utility and limitations of RASA using simulated and bacteriophage T7 data sets indicates that the method has numerous advantages over existing measures of signal. A first advantage is computational efficiency. A second advantage is that RASA employs known methods of statistical inference, providing measurable sensitivity and power. The performance of RASA is examined under various conditions of branching evolution as the number of characters, character states per character, and mutations per branch length are varied. RASA appears to provide an unbiased and reliable measure of phylogenetic signal, and the general approach promises to be useful in the development of new techniques that should increase the rigor and reliability of phylogenetic estimates.

Algorithms↗
PubMed1997

Laparoscopic Heller myotomy and fundoplication for achalasia.

OBJECTIVE: The goal of this study was to review the authors' results with laparoscopic cardiomyotomy and partial fundoplication for achalasia. SUMMARY BACKGROUND DATA: Pneumatic dilatation and botulinum toxin (BOTOX) injection of the lower esophageal sphincter largely have replaced cardiomyotomy for treatment of achalasia. After a brief experience with a thoracoscopic approach, the authors elected to perform cardiomyotomy laparoscopically, in combination with a partial fundoplication (anterior or posterior). PATIENTS AND METHODS: Forty patients were treated between July 1992 and November 1996. Thirty patients had previous therapy of achalasia, 21 with pneumatic dilation, 1 with BOTOX, 6 with balloon and BOTOX, and 2 with transthoracic cardiomyotomy. Three patients had previous laparoscopic fundoplication for gastroesophageal reflux. Symptom scores (0 = none to 4 = disabling) were obtained before surgery and after surgery. Barium swallows and esophagogastroduodenoscopy were performed in all patients. Esophageal motility study was performed in 36 patients. Laparoscopic Heller myotomy and fundoplication was performed through five upper abdominal trocars. A 7-cm myotomy extended 6 cm above the GE junction and 1 cm below the GE junction. A posterior fundoplication was performed in 32 patients, anterior fundoplication in 7 patients, and no fundoplication in 1 patient. Statistical inference was performed with a Wilcoxon signed rank test. RESULTS: Mean operative duration was 199 +/- 36.2 minutes. Mean hospital stay was 2.75 days (range, 1-13 days). Dysphagia was alleviated in all but four patients (90%), and regurgitation in all but two patients (95%) (p < 0.001). Chest pain and heartburn improved significantly (p < 0.01) as well. Intraoperative complications included mucosal laceration in six patients and hypercarbia in one. Postoperative pneumonia developed in two patients, and one patient had moderate hemorrhage from an esophageal ulcer 2 weeks after surgery. CONCLUSIONS: Laparoscopic cardiomyotomy and fundoplication appears to provide definitive treatment of achalasia with rapid rehabilitation and few complications.

Adolescent↗
PubMed1987

Analysis of dynamic computed tomography scan brain images.

Dynamic computed tomography (DCT) of the brain can be used to study the transit time of first passage of a bolus injection of intravenous contrast medium. Comparison of cerebral perfusion with corresponding sites in the left and right cerebral hemispheres is of diagnostic interest because a real difference may be indicative of differential damage. A method for estimating the mean transit time and approximating its standard error, by assuming a gamma function for the response curve and an appropriate error structure, is presented. Expressed as log-linear regression, estimation is achieved by maximum likelihood using a statistical package such as GLIM or SPSSX. Statistical comparison of the mean transit time to or between corresponding sites can be made; issues of model fit and biologic interpretation need to be considered as an integral part of statistical inference. These methods enable users of CT equipment (without specific software for estimation of mean transit time) to use any log-linear routine for diagnostic purposes. An example of the fit procedure and interpretation in the light of clinical evidence is given.

Brain↗
PubMedDate not supplied

Hepatocellular tumors with high signal on T1-weighted MR images: chemical shift MR imaging and histologic correlation.

We reviewed conventional and chemical shift MR images and histologic findings of seven proven primary hepatic masses that had higher signal than liver on T1-weighted images to determine if this necessarily indicates fat and if the presence of fat indicates malignancy. These seven masses included five hepatocellular carcinomas (HCCs), one focal nodular hyperplasia (FNH), and one fatty dysplastic nodule. An eighth solitary high signal mass without histologic proof had evidence of abundant fat on each of two chemical shift MR images 25 months apart. Only one of the five HCCs had chemical shift or histologic evidence of fat, while the FNH and dysplastic nodule each had both chemical shift and histologic confirmation of fat. The dysplastic nodule became more dysplastic and grew significantly within 14 months, but remained benign. The unproven fatty lesion decreased in size over 25 months and is therefore presumably benign. Although no statistical inferences can be drawn from this small correlative study, we have shown that HCC may have higher signal intensity than liver on T1-weighted images, whether or not it contains fat. Chemical shift techniques can confirm the presence of intratumoral fat and thus indicate a mass of hepatocellular origin, but the mass may be benign or malignant.

Biopsy↗
PubMed2003

Whole body irrigation for contraband bodypackers.

GOALS: Investigate outcomes of contraband body packers treated with whole bowel irrigation (WBI) using oral polyethylene glycol (PEG). Compare with prior studies of treatments using mild laxatives and/or observation. BACKGROUND: Drug smuggling via the gastrointestinal tract has risks including sudden death. Other studies have reported complication rates between 4% and 22%. STUDY: Retrospective case series of patients body packing contraband, and treated with WBI using PEG solution. Outcome measures include length of hospital stay (LOS) and complications. Statistical inferences using Spearman rank correlation and Fisher Exact tests. RESULTS: Sixteen patients with mean age 27.9 (SD 8.8). There were 2 complications (12.5%) and no deaths. There was no significant difference in complication frequency when compared with other reported treatment methods (P = 0.57, P = 0.48, P = 1.0). Mean LOS was 49.4 hours (SD 29.6). There was no correlation between mean LOS and either PEG dose (P = 0.89), drug type (P = 0.76), packet quantity (P = 0.34), or packet weight (P = 0.99). CONCLUSIONS: In this limited case series, WBI with PEG was used to treat contraband body packers with no higher complication frequency than other reported methods. The drug type, packet quantity, packet weight, and PEG dose did not correlate with the length of hospital stay.

Adolescent↗
PubMed2001

Early clinical results: SOUNDTEC implantable hearing device phase II study.

OBJECTIVE: To assess the safety and efficacy of a new semi-implantable electromagnetic hearing device, the SOUNDTEC Direct Drive Hearing System (DDHS), and to compare its performance with that of subjects' previously worn, optimally fit hearing aids. Preliminary results for the first 10 subjects are presented. STUDY DESIGN: The protocol specified in the Investigational Device Exemption is used in this ongoing FDA phase II 100-subject multicenter clinical trial. METHODS: For baseline, each subject is tested wearing his or her own optimally fit hearing aid in the ear to be implanted. Six-month postoperative outcome measures using the SOUNDTEC DDHS are compared with the baseline. Multiple objective and subjective outcomes (as listed under Results) were measured. RESULTS: When compared with the subjects' optimally fit hearing aids, the SOUNDTEC DDHS provided an average improvement of 52% in functional gain (250-6000 Hz), 22% in aided thresholds, 3.8% for speech discrimination in quiet, 17% for speech in noise, 13.1% in articulation index scores, 28% in aided benefit, 27.3% in sound quality of speech, and a 16.7% increase in overall subject satisfaction. In addition, with the SOUNDTEC DDHS, subjects reported absence of acoustic feedback, little or no occlusive effects, and more natural sound perception. CONCLUSION: Analysis of data on the first 10 subjects using the SOUNDTEC DDHS indicates positive outcomes regarding safety and efficacy, although the small sample size is not sufficient to permit valid statistical inferences to be drawn from our preliminary data. Results also demonstrate improvement in performance compared with the subjects' optimally fit hearing aids and an improvement in quality of life as demonstrated by objective and subjective tests and measures.

Aged↗