Long-term survivor mixture model with random effects: application to a multi-centre clinical trial of carcinoma

A mixture model incorporating long-term survivors has been adopted in the field of biostatistics where some individuals may never experience the failure event under study. The surviving fractions may be considered as cured. In most applications, the survival times are assumed to be independent. However, when the survival data are obtained from a multi-centre clinical trial, it is conceived that the environ mental conditions and facilities shared within clinic affects the proportion cured as well as the failure risk for the uncured individuals. It necessitates a long-term survivor mixture model with random effects. In this paper, the long-term survivor mixture model is extended for the analysis of multivariate failure time data using the generalized linear mixed model (GLMM) approach. The proposed model is applied to analyse a numerical data set from a multi-centre clinical trial of carcinoma as an illustration. Some simulation experiments are performed to assess the applicability of the model based on the average biases of the estimates formed. Copyright (C) 2001 John Wiley & Sons, Ltd.

Repeated occurrence of basal cell carcinoma of the skin and multifailure survival analysis: Follow-up data from the nambour skin cancer prevention trial

The aim of this study was to apply multifailure survival methods to analyze time to multiple occurrences of basal cell carcinoma (BCC). Data from 4.5 years of follow-up in a randomized controlled trial, the Nambour Skin Cancer Prevention Trial (1992-1996), to evaluate skin cancer prevention were used to assess the influence of sunscreen application on the time to first BCC and the time to subsequent BCCs. Three different approaches of time to ordered multiple events were applied and compared: the Andersen-Gill, Wei-Lin-Weissfeld, and Prentice-Williams-Peterson models. Robust variance estimation approaches were used for all multifailure survival models. Sunscreen treatment was not associated with time to first occurrence of a BCC (hazard ratio = 1.04, 95% confidence interval: 0.79, 1.45). Time to subsequent BCC tumors using the Andersen-Gill model resulted in a lower estimated hazard among the daily sunscreen application group, although statistical significance was not reached (hazard ratio = 0.82, 95% confidence interval: 0.59, 1.15). Similarly, both the Wei-Lin-Weissfeld marginal-hazards and the Prentice-Williams-Peterson gap-time models revealed trends toward a lower risk of subsequent BCC tumors among the sunscreen intervention group. These results demonstrate the importance of conducting multiple-event analysis for recurring events, as risk factors for a single event may differ from those where repeated events are considered.

Substrate-inhibited kinetics with catalyst deactivation in an isothermal CSTR. II. Multiple pseudosteady states and reactor failure

Analytical expressions are derived for the time and magnitude of failure of an isothermal CSTR with substrate-inhibited kinetics, caused by slow catalyst deactivation under three types of parallel and series mechanisms. Reactors operating at high space velocity are found to be most susceptible to early failure and poisoning by product is more dangerous than by reactant. The magnitude of the jump across steady states depends solely on the Langmuir-Hinshelwood kinetic parameters and a detailed analysis of reactor behavior during the jump itself is given.

Activation of beta(2)-adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C-protein in ventricular myocardium from patients with terminal heart failure

Background-Catecholamines hasten cardiac relaxation through beta-adrenergic receptors, presumably by phosphorylation of several proteins, but it is unknown which receptor subtypes are involved in human ventricle. We assessed the role of beta(1)- and beta(2)-adrenergic receptors in phosphorylating proteins implicated in ventricular relaxation. Methods and Results-Right ventricular trabeculae, obtained from freshly explanted hearts of patients with dilated cardiomyopathy (n=5) or ischemic cardiomyopathy (n=5), were paced at 60 bpm. After measurement of the contractile and relaxant effects of epinephrine (10 mu mol/L) or zinterol (10 mu mol/L), mediated through beta(2)-adrenergic receptors, and of norepinephrine (10 mu mol/L), mediated through beta(1)-adrenergic receptors, tissues were freeze clamped. We assessed phosphorylation of phospholamban, troponin I, and C-protein, as well as specific phosphorylation of phospholamban at serine 16 and threonine 17, Data did not differ between the 2 disease groups and were therefore pooled. Epinephrine, zinterol, and norepinephrine increased contractile force to approximately the same extent, hastened the onset of relaxation by 15+/-3%, 5+/-2%, and 20+/-3%, respectively, and reduced the time to half-relaxation by 26+/-3%, 21+/-3%, and 37+/-3%. These effects of epinephrine, zinterol, and norepinephrine were associated with phosphorylation (pmol phosphate/mg protein) of phospholamban 14+/-3, 12+/-4, and 12+/-3, troponin I 40+/-7, 33+/-7, and 31+/-6; and C-protein 7.2+/-1.9, 9.3 +/- 1.4, and 7.5 +/- 2.0. Phosphorylation of phospholamban occurred at both Ser16 and Thr17 residues through both beta(1)- and beta(2)-adrenergic receptors. Conclusions-Norepinephrine and epinephrine hasten human ventricular relaxation and promote phosphorylation of implicated proteins through both beta(1)- and beta(2)-adrenergic receptors, thereby potentially improving diastolic function.

Accelerating seismic energy release and evolution of event time and size statistics: Results from two heterogeneous cellular automaton models

The evolution of event time and size statistics in two heterogeneous cellular automaton models of earthquake behavior are studied and compared to the evolution of these quantities during observed periods of accelerating seismic energy release Drier to large earthquakes. The two automata have different nearest neighbor laws, one of which produces self-organized critical (SOC) behavior (PSD model) and the other which produces quasi-periodic large events (crack model). In the PSD model periods of accelerating energy release before large events are rare. In the crack model, many large events are preceded by periods of accelerating energy release. When compared to randomized event catalogs, accelerating energy release before large events occurs more often than random in the crack model but less often than random in the PSD model; it is easier to tell the crack and PSD model results apart from each other than to tell either model apart from a random catalog. The evolution of event sizes during the accelerating energy release sequences in all models is compared to that of observed sequences. The accelerating energy release sequences in the crack model consist of an increase in the rate of events of all sizes, consistent with observations from a small number of natural cases, however inconsistent with a larger number of cases in which there is an increase in the rate of only moderate-sized events. On average, no increase in the rate of events of any size is seen before large events in the PSD model.

On the heritability of inspection time and its covariance with IQ: A twin study

Using the classical twin design, this study investigates the influence of genetic factors on the large phenotypic variance in inspection time (IT), and whether the well established IT-IQ association can be explained by a common genetic factor. Three hundred ninety pairs of twins (184 monozygotic, MZ; 206 dizygotic, DZ) with a mean age of 16 years participated, and 49 pairs returned approximately 3 months, later for retesting. As in many IT studies, the pi figure stimulus was used and IT was estimated from the cumulative normal ogive. IT ranged from 39.4 to 774.1 ms (159 +/- 110.1 ms) with faster ITs (by an average of 26.9 ms) found in the retest session from which a reliability of .69 was estimated. Full-scale IQ (FIQ) was assessed by the Multidimensional Aptitude Battery (MAB) and ranged from 79 to 145 (111 +/- 13). The phenotypic association between IT and FIQ was confirmed (- .35) and bivariate results showed that a common genetic factor accounted for 36% of the variance in IT and 32% of the variance in FIQ. The maximum likelihood estimate of the genetic correlation was - .63. When performance and verbal IQ (PIQ & VIQ) were analysed with IT, a stronger phenotypic and genetic relationship was found between PIQ and IT than with VIQ. A large part of the IT variance (64%) was accounted for by a unique environmental factor. Further genetic factors were needed to explain the remaining variance in IQ with a small component of unique environmental variance present. The separability of a shared genetic factor influencing IT and IQ from the total genetic variance in IQ suggests that IT affects a specific subcomponent of intelligence rather than a generalised efficiency. (C) 2001 Elsevier Science Inc. All rights reserved.

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.

Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci

After ingestion of a standardized dose of ethanol, alcohol concentrations were assessed, over 3.5 hours from blood (six readings) and breath (10 readings) in a sample of 412 MZ and DZ twins who took part in an Alcohol Challenge Twin Study (ACTS). Nearly all participants were subsequently genotyped on two polymorphic SNPs in the ADH1B and ADH1C loci known to affect in vitro ADH activity. In the DZ pairs, 14 microsatellite markers covering a 20.5 cM region on chromosome 4 that includes the ADH gene family were assessed, Variation in the timed series of autocorrelated blood and breath alcohol readings was studied using a bivariate simplex design. The contribution of a quantitative trait locus (QTL) or QTL's linked to the ADH region was estimated via a mixture of likelihoods weighted by identity-by-descent probabilities. The effects of allelic substitution at the ADH1B and ADH1C loci were estimated in the means part of the model simultaneously with the effects sex and age. There was a major contribution to variance in alcohol metabolism due to a QTL which accounted for about 64% of the additive genetic covariation common to both blood and breath alcohol readings at the first time point. No effects of the ADH1B*47His or ADH1C*349Ile alleles on in vivo metabolism were observed, although these have been shown to have major effects in vitro. This implies that there is a major determinant of variation for in vivo alcohol metabolism in the ADH region that is not accounted for by these polymorphisms. Earlier analyses of these data suggested that alcohol metabolism is related to drinking behavior and imply that this QTL may be protective against alcohol dependence.

Use of pulse transit time to distinguish respiratory events from tidal breathing in sleeping children

Study objectives: Currently, esophageal pressure monitoring is the "gold standard" measure for inspiratory efforts, hut its invasive nature necessitates a better tolerated and noninvasive method to be used on children. Pulse transit time (PTT) has demonstrated its potential as a noninvasive surrogate marker for inspiratory efforts. The principle velocity determinant of PTT is the change in stiffness of the arterial wall and is inversely correlated to BP. Moreover, PTT has been shown to identify changes in inspiratory effort via the BP fluctuations induced by negative pleural pressure swings. In this study, the capability of PTT to classify respiratory, events during sleep as either central or obstructive in nature was investigated. Setting and participants: PTT measure was used in adjunct to routine overnight polysomnographic studies performed on 33 children (26 boys and 7 girls; mean +/- SD age, 6.7 +/- 3.9 years). The accuracy of PTT measurements was then evaluated against scored corresponding respiratory events in the polysomnography recordings. Results: Three hundred thirty-four valid respiratory events occurred and were analyzed. One hundred twelve obstructive events (OEs) showed a decrease in mean PTT over a 10-sample window that had a probability of being correctly ranked below the baseline PTT during tidal breathing of 0.92 (p < 0.005); 222 central events (CEs) showed a decrease in the variance of PTT over a 10-sample window that had a probability of being ranked below the baseline PTT of 0.94 (p < 0.005). This indicates that, at a sensitivity of 0.90, OEs can be detected with a specificity of 0.82 and CEs can be detected with a specificity of 0.80. Conclusions: PTT is able to categorize CEs and OEs accordingly in the absence of motion artifacts, including hypopneas. Hence, PTT shows promise to differentiate respiratory, events accordingly and can be an important diagnostic tool in pediatric respiratory sleep studies.< 0.005); 222 central events (CEs) showed a decrease in the variance of PTT over a 10-sample window that had a probability of being ranked below the baseline PTT of 0.94 (p < 0.005). This indicates that, at a sensitivity of 0.90, OEs can be detected with a specificity of 0.82 and CEs can be detected with a specificity of 0.80. Conclusions: PTT is able to categorize CEs and OEs accordingly in the absence of motion artifacts, including hypopneas. Hence, PTT shows promise to differentiate respiratory, events accordingly and can be an important diagnostic tool in pediatric respiratory sleep studies.');"

Nephron number, hypertension, renal disease, and renal failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed.

Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure

Administration of human recombinant erythropoietin ( EPO) at time of acute ischemic renal injury ( IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa ( DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats ( N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation ( T0), or post-treated ( 6 h after the onset of reperfusion, T6) with EPO ( 5000 IU/kg), DPO ( 25 mu g/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.08 +/- 0.03mmol/l vs EPO-IRI 0.04 +/- 0.01mmol/l, P = 0.01). Delayed administration of DPO or EPO ( T6) also significantly abrogated subsequent renal dysfunction ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.06 +/- 0.01mmol/l vs EPO-IRI 0.03 +/- 0.03mmol/l, P = 0.01). There was also significantly decreased tissue injury ( apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.