An EM-based Semi-Parametric Mixture Model Approach to the Regression Analysis of Competing-Risks Data

We consider a mixture model approach to the regression analysis of competing-risks data. Attention is focused on inference concerning the effects of factors on both the probability of occurrence and the hazard rate conditional on each of the failure types. These two quantities are specified in the mixture model using the logistic model and the proportional hazards model, respectively. We propose a semi-parametric mixture method to estimate the logistic and regression coefficients jointly, whereby the component-baseline hazard functions are completely unspecified. Estimation is based on maximum likelihood on the basis of the full likelihood, implemented via an expectation-conditional maximization (ECM) algorithm. Simulation studies are performed to compare the performance of the proposed semi-parametric method with a fully parametric mixture approach. The results show that when the component-baseline hazard is monotonic increasing, the semi-parametric and fully parametric mixture approaches are comparable for mildly and moderately censored samples. When the component-baseline hazard is not monotonic increasing, the semi-parametric method consistently provides less biased estimates than a fully parametric approach and is comparable in efficiency in the estimation of the parameters for all levels of censoring. The methods are illustrated using a real data set of prostate cancer patients treated with different dosages of the drug diethylstilbestrol. Copyright (C) 2003 John Wiley Sons, Ltd.

Quality of care of patients hospitalized with congestive heart failure

Background: Congestive heart failure (CHF) is an increasingly prevalent poor-prognosis condition for which effective interventions are available. It is -therefore important to determine the extent to which patients with CHF receive appropriate care in Australian hospitals and identify ways for improving suboptimal care, if it exists. Aim: To evaluate the quality of in-hospital acute care of patients with CHF using explicit quality indicators based on published guidelines. Methods: A retrospective case note review was -performed, involving 216 patients admitted to three teaching hospitals in Brisbane, Queensland, Australia, between October 2000 and April 2001. Outcome measures were process-of-care quality -indicators calculated as proportions of all, or strongly -eligible (ideal), patients who received -specific interventions. Results: Assessment of underlying causes and acute precipitating factors was undertaken in 86% and 76% of patients, respectively, and objective evaluation of left ventricular function was performed in 62% of patients. Prophylaxis for deep venous thrombosis (DVT) was used in only 29% of ideal patients. Proportions of ideal patients receiving pharmacological treatments at discharge were: (i) angiotensin--converting enzyme inhibitors (ACEi) (82%), (ii) target doses of ACEi (61%), (iii) alternative vasodilators in patients ineligible for ACEi (20%), (iv) beta-blockers (40%) and (v) warfarin (46%). Conclusions: Opportunities exist for improving quality of in-hospital care of patients with CHF, -particularly for optimal prescribing of: (i) DVT prophylaxis, (ii) ACEi, (iii) second-line vasodilators, (iv) beta-blockers and (v) warfarin. More research is needed to identify methods for improving quality of in-hospital care.

Etiology of ovarian failure in blepharophimosis ptosis epicanthus inversus syndrome: FOXL2 is a conserved, early-acting gene in vertebrate ovarian development

Blepharophimosis ptosis epicanthus inversus syndrome (BPES) is a human disorder caused by mutations in the forkhead transcription factor gene FOXL2 and is characterized by facial dysmorphology combined in some cases with ovarian failure. To better understand the role of FOXL2 in the etiology of ovarian failure in BPES, we examined its expression in embryonic ovaries of mice, chickens, and red-eared slider turtles, representatives of three phylogenetically distant vertebrate groups that have different mechanisms of sex determination. Expression of Foxl2 was detected in early ovaries of all three species around the time of sex determination and was associated with both somatic and germ cell populations in mice. Expression was sexually dimorphic in all cases. Sequence analysis of turtle and chicken FoxL2 orthologues indicated an unusually high degree of structural conservation during evolution. FoxL2 was found to be autosomal in chickens, and therefore unlikely to represent the dominant ovarian-determining gene that has been postulated to exist as a possible explanation for female heterogamety in birds. Our observations suggest that BPES may result from early abnormalities in regulating the development of the fetal ovary, rather than premature degeneration of the postnatal or adult ovary. Further, our results suggest that FOXL2 is a highly conserved early regulator of vertebrate ovarian development.

Computational differentiation of N-terminal signal peptides and transmembrane helices

Signal peptides and transmembrane helices both contain a stretch of hydrophobic amino acids. This common feature makes it difficult for signal peptide and transmembrane helix predictors to correctly assign identity to stretches of hydrophobic residues near the N-terminal methionine of a protein sequence. The inability to reliably distinguish between N-terminal transmembrane helix and signal peptide is an error with serious consequences for the prediction of protein secretory status or transmembrane topology. In this study, we report a new method for differentiating protein N-terminal signal peptides and transmembrane helices. Based on the sequence features extracted from hydrophobic regions (amino acid frequency, hydrophobicity, and the start position), we set up discriminant functions and examined them on non-redundant datasets with jackknife tests. This method can incorporate other signal peptide prediction methods and achieve higher prediction accuracy. For Gram-negative bacterial proteins, 95.7% of N-terminal signal peptides and transmembrane helices can be correctly predicted (coefficient 0.90). Given a sensitivity of 90%, transmembrane helices can be identified from signal peptides with a precision of 99% (coefficient 0.92). For eukaryotic proteins, 94.2% of N-terminal signal peptides and transmembrane helices can be correctly predicted with coefficient 0.83. Given a sensitivity of 90%, transmembrane helices can be identified from signal peptides with a precision of 87% (coefficient 0.85). The method can be used to complement current transmembrane protein prediction and signal peptide prediction methods to improve their prediction accuracies. (C) 2003 Elsevier Inc. All rights reserved.

Acute liver failure in children: A regional experience

Objective: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia. Methodology: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia. Results: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long-term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function. Conclusions: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.

A practical guide to exercise training for heart failure patients

Background: Exercise training has been shown to improve exercise capacity in patients with heart failure. We sought to examine the optimal strategy of exercise training for patients with heart failure. Methods: Review of the published data on the characteristics of the training program, with comparison of physiologic markers of exercise capacity in heart failure patients and healthy individuals and comparison of the change in these characteristics after all exercise training program. Results: Many factors, including the duration, supervision, and venue of exercise training; the volume of working muscle; the delivery mode (eg, continuous vs. intermittent exercise), training intensity; and the concurrent effects of medical treatments may influence the results of exercise training in heart failure. Starting in an individually prescribed and safely monitored hospital-based program, followed by progression to an ongoing and progressive home program of exercise appears to be the best solution to the barriers of anxiety, adherence, and ease of access encountered by the heart failure patient. Conclusions: Various exercise training programs have been shown to improve exercise capacity and symptom status in heart failure, but these improvements may only be preserved with an ongoing maintenance program.

Biaxial failure model for fiber reinforced concrete

Steel fiber reinforced concrete (SFRC) is widely applied in the construction industry. Numerical elastoplastic analysis of the macroscopic behavior is complex. This typically involves a piecewise linear failure curve including corner singularities. This paper presents a single smooth biaxial failure curve for SFRC based on a semianalytical approximation. Convexity of the proposed model is guaranteed so that numerical problems are avoided. The model has sufficient flexibility to closely match experimental results. The failure curve is also suitable for modeling plain concrete under biaxial loading. Since this model is capable of simulating the failure states in all stress regimes with a single envelope, the elastoplastic formulation is very concise and simple. The finite element implementation is developed to demonstrate the conciseness and the effectiveness of the model. The computed results display good agreement with published experimental data.

Left ventricular dyssynchrony predicts benefit of cardiac resynchronization therapy in patients with end-stage heart failure before pacemaker implantation

We evaluated patients with end-stage heart failure who have a high likelihood of response to cardiac resynchronization therapy (biventricular pacing). It appears that 20% of patients do not respond to this expensive therapy despite the use of selection criteria (dilated cardiomyopathy, heart failure, New York Heart Association class II or IV, left ventricular election fraction 120 ms). The presence of left ventricular dys-synchrony is needed to result in improvement after cardiac resynchronization therapy. (C)2003 by Excerpta Medica, Inc.

Mechanisms of exercise training in patients with heart failure

Background The reduction of exercise capacity because of fatigue and dyspnea in patients with heart failure can be improved with exercise training. We sought to examine the mechanisms of exercise training, as an adjunctive treatment strategy for patients with heart failure. Methods a reviewed the published data on the possible mechanisms of effect of exercise training in heart failure. Results Symptoms of heart failure may be explained on the basis of abnormal skeletal muscle perfusion and structure and endothelial function. Exercise training has been shown to engender changes in muscle structure and biochemistry and vascular function, although effects on cardiac function have not been detected uniformly and may require longer training periods. Conclusions A suitable, long-term program of exercise training may reverse unfavorable interactions among the heart, vessels, and skeletal muscles. These improvements may be preserved with an ongoing maintenance program.