The Design of Intervention Trials Involving Recurrent and Terminal Events

The final publication (Wu, Longyang, and Richard J. Cook. "The Design of Intervention Trials Involving Recurrent and Terminal Events." Statistics in Biosciences 5(2) (2013): 261-285) is available at Springer via http://dx.doi.org/10.1007/s12561-013-9083-zClinical trials are often designed to assess the effect of therapeutic interventions on the incidence of recurrent events in the presence of a dependent terminal event such as death. Statistical methods based on multistate analysis have considerable appeal in this setting since they can incorporate changes in risk with each event occurrence, a dependence between the recurrent event and the terminal event, and event-dependent censoring. To date, however, there has been limited development of statistical methods for the design of trials involving recurrent and terminal events. Based on the asymptotic distribution of regression coefficients from a multiplicative intensity Markov regression model, we derive sample size formulas to address power requirements for both the recurrent and terminal event processes. We consider the design of trials for which separate marginal hypothesis tests are of interest for the recurrent and terminal event processes and deal with both superiority and non-inferiority tests. Simulation studies confirm that the designs satisfy the nominal power requirements in both settings, and an application to a trial evaluating the effect of a bisphosphonate on skeletal complications is given for illustration.Natural Sciences and Engineering Research Council of Canada (RJC RGPIN 155849, JFL RGPIN 8597); Canadian Institutes for Health Research (FRN 13887); Canada Research Chair (Tier 1) – CIHR funded (950-226626

Marginal Methods for Multivariate Time to Event Data

This thesis considers a variety of statistical issues related to the design and analysis of clinical trials involving multiple lifetime events. The use of composite endpoints, multivariate survival methods with dependent censoring, and recurrent events with dependent termination are considered. Much of this work is based on problems arising in oncology research. Composite endpoints are routinely adopted in multi-centre randomized trials designed to evaluate the effect of experimental interventions in cardiovascular disease, diabetes, and cancer. Despite their widespread use, relatively little attention has been paid to the statistical properties of estimators of treatment effect based on composite endpoints. In Chapter 2 we consider this issue in the context of multivariate models for time to event data in which copula functions link marginal distributions with a proportional hazards structure. We then examine the asymptotic and empirical properties of the estimator of treatment effect arising from a Cox regression model for the time to the first event. We point out that even when the treatment effect is the same for the component events, the limiting value of the estimator based on the composite endpoint is usually inconsistent for this common value. The limiting value is determined by the degree of association between the events, the stochastic ordering of events, and the censoring distribution. Within the framework adopted, marginal methods for the analysis of multivariate failure time data yield consistent estimators of treatment effect and are therefore preferred. We illustrate the methods by application to a recent asthma study. While there is considerable potential for more powerful tests of treatment effect when marginal methods are used, it is possible that problems related to dependent censoring can arise. This happens when the occurrence of one type of event increases the risk of withdrawal from a study and hence alters the probability of observing events of other types. The purpose of Chapter 3 is to formulate a model which reflects this type of mechanism, to evaluate the effect on the asymptotic and finite sample properties of marginal estimates, and to examine the performance of estimators obtained using flexible inverse probability weighted marginal estimating equations. Data from a motivating study are used for illustration. Clinical trials are often designed to assess the effect of therapeutic interventions on occurrence of recurrent events in the presence of a dependent terminal event such as death. Statistical methods based on multistate analysis have considerable appeal in this setting since they can incorporate changes in risk with each event occurrence, a dependence between the recurrent event and the terminal event and event-dependent censoring. To date, however, there has been limited methodology for the design of trials involving recurrent and terminal events, and we addresses this in Chapter 4. Based on the asymptotic distribution of regression coefficients from a multiplicative intensity Markov regression model, we derive sample size formulae to address power requirements for both the recurrent and terminal event processes. Superiority and non-inferiority trial designs are dealt with. Simulation studies confirm that the designs satisfy the nominal power requirements in both settings, and an application to a trial evaluating the effect of a bisphosphonate on skeletal complications is given for illustration

Variation in the Glucose Transporter gene <i>SLC2A2 </i>is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine

Simple fabrication of copper surfaces with tunable wettability and multi-level structures via one-step method

Simple fabrication of copper surfaces with tunable wettability and multi-level structures via one-step metho

PKNOX2 Is Associated With Formal Thought Disorder in Schizophrenia: A Meta-Analysis of Two Genome-Wide Association Studies

Formal thought disorder (FTD), or disorganized speech, is one of the central signs of schizophrenia; however, little is known about the etiology of FTD. To identify new genetic loci associated with FTD, we conducted the first genome-wide association meta-analysis of two datasets of 835 cases of FTD and 2,694 controls with 729,454 single-nucleotide polymorphisms (SNPs). Logistic regression analysis of FTD as a binary trait, adjusted for age and sex, was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 61 SNPs associated with FTD with p \u3c 10-4. The most significant association with FTD was observed with rs1783925 (p = 4.4 × 10-7) within PKNOX2 gene at 11q24.2 while the second interesting locus was rs2277644 (p = 1.18 × 10-5) within MYH13 at 17p13. Haplotype analyses of PKNOX2 and MYH13 loci further supported the associations with FTD. The third locus was PHF2 at 9q22.31 (the top SNP was rs12238738 with p = 2.08 × 10-5) while the fourth locus was GPC6 at 13q32 (the top SNP was rs17196161 with p = 3.12 × 10-5). In conclusion, we identified four new loci (PKNOX2, MYH13, PHF2, and GPC6) associated with FTD. These findings offer the potential for new insights into the pathogenesis of FTD and schizophrenia

Antibacterial behaviors of Cu2O particles with controllable morphologies in acrylic coatings

Antibacterial behaviors of Cu2O particles with controllable morphologies in acrylic coating

Preparation and Properties of Superhydrophobizted Sprayed Zn-Al Coating

A superhydrophobic ZnAl coating was prepared by the electric arc spraying technology and then surface modification by stearic acid/ethanol. The surface wettability, morphology and chemical structure of the ZnAl coating before and after modification were characterized by contact angle measurement (OCA-20), scanning electron microscope (SEM) and artificial FTIR spectrometer (ATR), respectively. The impedance spectrum and polarization curves of the coatings were measuared by electrochemical workstation (Solartron Analytical) with three electrodes system. The results show that the as sprayed ZnAl coating consists of irregular micro- and nano-sized alloy particles and pores, and exhibits clear hydrophilicity, which may be ascribed to the high surface energy of metallic coating. After the surface modification with stearic acid, the static contact angle of the coating reached 153.8° with a rolling angle less than 10°, because there exsited a large number of hydrophobic long alkyl chains on the surface of the modified ZnAl coating. In addition, the surface modification could significantly enhance the corrosion resistance of ZnAl coating due to that the thin hydrophobic film plays an important role in supression of the fall off and dissolution of corrosion products on the ZnAl coating, leading to the increase of charge transfer resistance and the corrosion current density

Low Drag Porous Ship with Superhydrophobic and Superoleophilic Surface for Oil Spills Cleanup

To efficiently remove and recycle oil spills, we construct aligned ZnO nanorod arrays on the surface of the porous stainless steel wire mesh to fabricate a porous unmanned ship (PUS) with properties of superhydrophobicity, superoleophilicity, and low drag by imitating the structure of nonwetting leg of water strider. The superhydrophobicity of the PUS is stable, which can support 16.5 cm water column with pore size of 100 μm. Water droplet can rebound without adhesion. In the process of oil/water separation, when the PUS contacts with oil, the oil is quickly pulled toward and penetrates into the PUS automatically. The superhydrophobicity and low water adhesion force of the PUS surface endow the PUS with high oil recovery capacity (above 94%) and drag-reducing property (31% at flowing velocity of 0.38m/s). In addition, the PUS has good corrosion resistance and reusability. We further investigate the wetting behavior of water and oil, oil recovery capacity, drag-reducing property, and corrosion resistance of the PUS after oil absorbed. The PUS surface changes significantly from superhydrophobic to hydrophobic after absorbing oil. However, the oil absorbed PUS possesses better drag-reducing property and corrosion resistance due to the changes of the motion state of the water droplets

Ecological Compensation in the Context of Carbon Neutrality: A Case Involving Service Production-Transmission and Distribution-Service Consumption

Carbon ecological compensation is essential to coordinate regional environmental protection, reduce the gap between the economic development of protected areas and beneficiary areas, and achieve carbon neutrality. This paper proposed a theoretical framework for ecological compensation using the theories of carbon balance, externality, ecosystem services, and carbon trading mechanisms. Based on the analysis of the ecological compensation priority sequence in Henan Province, the suppliers and consumers of carbon sequestration were identified, and cross-regional ecological compensation was realized through ecosystem services flow. The results showed that the carbon sequestration supply in Henan Province was characterized as being high in the west and low in the east, while the demand was the opposite. Affected by the suitable environmental conditions, many areas had an ecological surplus pattern, and the carbon sequestration supply was more significant than the demand. Central and south-western Henan Province were distinct ecological compensation payment areas and receiving areas, respectively. Nanyang, which had the largest carbon sequestration flow and the largest ecological contribution to other regions, received the highest ecological compensation fund of CNY 4.069 billion. This study can provide decision support for carbon ecological compensation in the context of carbon neutrality