Planning of randomized early detection trials

Consider a randomized clinical trial to evaluate the benefit of screening an asymptomatic population. Suppose that the subjects are randomized into a usual care and a study group. The study group receives one or more periodic early detection examinations aimed at diagnosing disease early, when there are no signs or symptoms. Early detection clinical trials differ from therapeutic trials in that power is affected by: i) the number of exams, ii) the time between exams and iii) the ages at which exams will be given. These design options do not exist in therapeutic trials. Furthermore; long-term follow-up may result in a reduction of power. In general, power increases with number of examinations, and the optimal follow-up time is dependent on the spacing between examinations. Clinical trials in which the usual care group receives benefit are also discussed. Two designs are discussed, for example the 'up-front design' in which all subjects receive an initial exam and then are randomized to the usual care and study groups and the 'close-out design' in which the usual care group receives an exam which is timed to be given at the same time as the last exam in the study group. Both families of designs significantly reduce the power. Power calculations are made for two clinical trials, which actually used these two designs.     

Individually randomized intervention trials for disease prevention and control

It is argued that randomized, controlled trials should fulfil a critical role in the identification of practical approaches to the prevention and control of chronic diseases. Because of the great public health potential of chemopreventive and behavioural approaches to chronic disease prevention there is need for a major interdisciplinary scientific effort aimed at intervention development. Because of the cost and duration of controlled trials to evaluate specific interventions there is a need for well-conducted feasibility, pilot and intermediate outcome trials, to inform and to justify corresponding full-scale trials having clinical disease outcomes. Compared to therapeutic trials, prevention trials need to have a greater emphasis on overall benefit versus risk assessment. Such trials need to be large enough, and of sufficient duration, to yield powerful tests of key hypotheses, and informative benefit versus risk summary statements. These requirements have a range of implications for intervention trial design, conduct, monitoring and reporting, which are reviewed and discussed. The clinical trial component of the ongoing Women's Health Initiative provides illustration throughout this discussion.     

Cluster randomized trials in general (family) practice research

Cluster randomized trials are increasingly common in general practice (family medicine). This paper will consider the design and analysis of such trials and emphasize the similarities and differences with trials in education, heath promotion and public health. Issues discussed are the estimation and range of values of the intra-cluster correlation coefficient found in general practice, and the associated sample size problems. There are problems with widely varying numbers of subjects per cluster, which leads to planning and analysis difficulties. Ethical issues in these trials, and considerations such as the principle of intention to treat are also considered. An example of the type of analysis available for a continuous outcome variable is given, and the available software is summarized briefly.     

Evaluation of various additives at Jubail phase I during reliability trials

Jubail Phase I consists of 6 dual purpose units, each having a boiler, turbine and desalination unit. Total design output is 30.06 mIgd of distillate and 360 MW of power, each desalination unit designed to produce 5.01 mIgd at maximum brine recycle temperature of 90.6°C using polyphosphate as the scale control additive. Long operating experience with polyphosphate [1] showed it to be a moderately effective scale control additive. It was decided to evaluate other additives available on the market, compare their effectiveness for scale control, and to conclude which one would give longest operating time before the plant performance ratio drops necessitating acid cleaning. Belgard EVN was employed as the scale control additive during commissioning and reliability trials of unit Nos. 1 and 3. Albrivap B and Flocon 247 were used on unit Nos. 2 and 4, respectively. This paper presents experience with these additives during the first four reliability trials.     

Polyunsaturated fatty acids and infant visual development: A critical appraisal of randomized clinical trials

At the Consensus and Controversies Conference held in Barcelona in November 1996, one of the sessions focused on an evaluation of the effects of dietary polyunsaturated fatty acids (PUFA) on infant visual development. The intervention trials in preterm and term infants were reviewed and discussed in detail. Results of these trials, particularly those in term infants, were inconsistent; much discussion occurred concerning the causes of these diverse results. We attempt to reflect, rather than report exactly, the discussion relating to these issues and address the clinical trials according to recently published guidelines for conduct and reporting of randomized clinical trials (RCT). Compared with these recent guidelines, the published papers of RCT involving PUFA and visual function are often incomplete, making it difficult to assess if we can have a high degree of confidence in the reported effects (or lack of effects). Despite this, valuable data relating to the effect of diet on the visual development of infants were obtained. Our evaluation of the trials to date suggests that the definitive answer to the degree to which dietary long-chain PUFA is likely to influence visual development may only be resolved with impeccably conducted RCT.     

Relative efficiency of unequal cluster sizes for variance component estimation in cluster randomized and multicentre trials

Cluster randomized and multicentre trials evaluate the effect of a treatment on persons nested within clusters, for instance patients within clinics or pupils within schools. Although equal sample sizes per cluster are generally optimal for parameter estimation, they are rarely feasible. This paper addresses the relative efficiency (RE) of unequal versus equal cluster sizes for estimating variance components in cluster randomized trials and in multicentre trials with person randomization within centres, assuming a quantitative outcome. Starting from maximum likelihood estimation, the RE is investigated numerically for a range of cluster size distributions. An approximate formula is presented for computing the RE as a function of the mean and variance of cluster sizes and the intraclass correlation. The accuracy of this approximation is checked and found to be good. It is concluded that the loss of efficiency for variance component estimation due to variation of cluster sizes rarely exceeds 20% and can be compensated by sampling 25% more clusters.     

Effects of isoflavones (soy phyto-estrogens) on serum lipids: a meta-analysis of randomized controlled trials

Objectives

To determine the effects of isoflavones (soy phyto-estrogens) on serum total cholesterol (TC), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride (TG).

Methods

We searched electronic databases and included randomized trials with isoflavones interventions in the forms of tablets, isolated soy protein or soy diets. Review Manager 4.2 was used to calculate the pooled risk differences with fixed effects model.

Results

Seventeen studies (21 comparisons) with 853 subjects were included in this meta-analysis. Isoflavones tablets had insignificant effects on serum TC, 0.01 mmol/L (95% CI: -0.17 to 0.18, heterogeneity p = 1.0); LDL, 0.00 mmol/L (95% CI: -0.14 to 0.15, heterogeneity p = 0.9); HDL, 0.01 mmol/L (95% CI: -0.05 to 0.06, heterogeneity p = 1.0); and triglyceride, 0.03 mmol/L (95% CI: -0.06 to 0.12, heterogeneity p = 0.9). Isoflavones interventions in the forms of isolated soy protein (ISP), soy diets or soy protein capsule were heterogeneous to combine.

Conclusions

Isoflavones tablets, isolated or mixtures with up to 150 mg per day, seemed to have no overall statistical and clinical benefits on serum lipids. Isoflavones interventions in the forms of soy proteins may need further investigations to resolve whether synergistic effects are necessary with other soy components.

     

Simple maximum likelihood estimates of efficacy in randomized trials and before-and-after studies, with implications for meta-analysis

Efficacy, which we define as the effect of receiving intervention on health outcomes among a group of subjects, is the quantity of interest for many investigators. In contrast, intent-to-treat analyses in randomized trials and their analogue for observational before-and-after studies compare outcomes between randomization groups or before-and-after time periods. When there is switching of interventions, estimates based on intent-to-treat are biased for estimating efficacy. By constructing a model based on potential outcomes, one can make reasonable assumptions to estimate efficacy under 'all-or-none' switching of interventions in which switching occurs immediately after randomization or at the start of the time period. This paper reviews the basic methodology, with emphasis on simple maximum likelihood estimates that arise with completely observed outcomes, partially missing binary outcomes, and discrete-time survival outcomes. Particular attention is paid to estimating efficacy in meta-analysis, where the interpretation is much more straightforward than with intent-to-treat analyses.     

Evaluation of change in CD4+ cell counts in AIDS clinical trials

To evaluate the antiretroviral activity of antiretroviral agents and to compare the effects of two different antiretroviral agents, we propose a non-parametric mixed-effects model to investigate change of CD4+ counts. The proposed model and methods are applied to analyse the data from PACTG345 study. Population and individual patterns of change of CD4+ counts and a reference band are obtained. Our results indicate that treatment with high-dose ritonavir is significantly superior compared with low-dose ritonavir.     

Sequential comparison of two treatments in clinical trials:a decision theoretic approach based on randomized play-the-winner rule

In the context of comparing two treatments in clinical trials randomized play-the-winner rule is used with the goal of treating more patients by the better treatment On its basis we give two decision rules by introducing stopping rule Some performance characteristics of one of the decision rules are discussed and examined .A minimax rule is suggested Finally some exact and asymptotic properties of the decision rule is derived     

Structural mean models for compliance analysis in randomized clinical trials and the impact of errors on measures of exposure

Partial compliance with assigned treatment regimes is common in drug trials and calls for a causal analysis of the effect of treatment actually received. As such observed exposure is no longer randomized, selection bias must be carefully accounted for. The framework of potential outcomes allows this by defining a subject-specific treatment-free reference outcome, which may be latent and is modelled in relation to the observed (treated) data. Causal parameters enter these structural models explicitly. In this paper we review recent progress in randomization-based inference for structural mean modelling, from the additive linear model to the structural generalized linear models. An arsenal of tools currently available for standard association regression has steadily been developed in the structural setting, providing many parallel features to help randomization-based inference. We argue that measurement error on exposure is an important practical complication that has, however, not yet been addressed. We show how standard additive linear structural mean models are robust against unbiased measurement error and how efficient, asymptotically unbiased inference can be drawn when the degree of measurement error bias is known. The impact of measurement error is illustrated in a blood pressure example and finite sample properties are verified by simulation. We end with a plea for more and careful use of this methodology and point to directions for further development.     

Estimating treatment effects from randomized clinical trials with noncompliance and loss to follow-up: the role of instrumental variable methods

Perfectly implemented randomized clinical trials, particularly of complex interventions, are extremely rare. Almost always they are characterized by imperfect adherence to the randomly allocated treatment and variable amounts of missing outcome data. Here we start by describing a wide variety of examples and then introduce instrumental variable methods for the analysis of such trials. We concentrate mainly on situations in which compliance is all or nothing (either the patient receives the allocated treatment or they do not--in the latter case they may receive no treatment or a treatment other than the one allocated). The main purpose of the review is to illustrate the use of latent class (finite mixture) models, using maximum likelihood, for complier-average causal effect estimation under varying assumptions concerning the mechanism of the missing outcome data.     

Ionizable interpenetrating polymer networks of carboxymethyl cellulose and polyacrylic acid: Evaluation of water uptake

A semi interpenetrating polymer network (IPN) of carboxymethyl cellulose (CMC) and crosslinked polyacrylic acid (PAA) has been prepared and its water‐sorption capacity has been evaluated as a function of chemical architecture of the IPN, pH, and temperature of the swelling medium. The water uptake potential of the IPNs has also been investigated in inorganic salt containing aqueous solutions and simulated biological fluids. The IPN was characterized by IR spectral analysis, and the network parameters such as average molecular weight between crosslinks (M_c), crosslink density (q), and number of elastically effective chains (V_e) have been evaluated by water‐sorption measurements. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 2054–2065, 2004     

Evaluation of disulfide chain extender effect on the mechanical properties of unsaturated polyurethane‐urea networks

4‐Aminophenyl disulfide and bis(4‐aminophenyl)methane chain extenders containing hydroxyl‐terminated polybutadiene‐based polyurethane‐ureas are prepared one‐shot to explore the effect of the chain extender structure on the elastomers mechanical properties. However, the results revealed that the participation of the disulfide chain extender in side reactions like thiol‐ene and proton abstraction prevented disulfide metathesis reaction due to decomposing chain extender in the polyurethane‐urea matrix. Also, these side reactions improved the phase mixing via chemical crosslinking between polyurethane‐ureas soft and hard segments, too. Tensile test results showed higher stress strength of the elastomers in the presence of the disulfide chain extender in comparison with the nondisulfide bond containing elastomers. This result was in agreement with the observed result in dynamical mechanical analysis. Dynamic mechanical analysis results established that the absence of the disulfide bond in the polyurethane‐urea matrix led to the higher viscous modulus. The swelling test revealed chemical crosslinking increased in the presence of the disulfide bond. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46309.     

Efficacy and safety of turmeric and curcumin in lowering blood lipid levels in patients with cardiovascular risk factors: a meta-analysis of randomized controlled trials

Background

Dyslipidemia is an important and common cardiovascular risk factor in the general population. The lipid-lowering effects of turmeric and curcumin are unconfirmed. We performed a meta-analysis to assess the efficacy and safety of turmeric and curcumin in lowering blood lipids in patients at risk of cardiovascular disease (CVD).

Methods

A comprehensive literature search was conducted on PubMed, Embase, Ovid, Medline and Cochrane Library databases to identify randomized controlled trials (published as of November 2016) that assessed the effect of turmeric and curcumin on blood lipid levels including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Pooled standardized mean difference (SMD) with 95% confidence interval (CI) was used to assess the effect.

Results

The analysis included 7 eligible studies (649 patients). Turmeric and curcumin significantly reduced serum LDL-C (SMD = ?0.340, 95% confidence interval [CI]: ?0.530 to ?0.150, P < 0.0001) and TG (SMD = ?0.214, 95% CI: ?0.369 to ?0.059, P = 0.007) levels as compared to those in the control group. These may be effective in lowering serum TC levels in patients with metabolic syndrome (MetS, SMD = ?0.934, 95% CI: ?1.289 to ?0.579, P < 0.0001), and turmeric extract could possibly have a greater effect on reducing serum TC levels (SMD = ?0.584, 95% CI: ?0.980 to ?0.188, P = 0.004); however, the efficacy is yet to be confirmed. Serum HDL-C levels were not obviously improved. Turmeric and curcumin appeared safe, and no serious adverse events were reported in any of the included studies.

Conclusions

Turmeric and curcumin may protect patients at risk of CVD through improving serum lipid levels. Curcumin may be used as a well-tolerated dietary adjunct to conventional drugs. Further research is required to resolve uncertainties related to dosage form, dose and medication frequency of curcumin.

     

The design of multicentre trials

The analysis of data collected in multicentre trials offers challenges because the data from the individual centres must be combined in some way to give an overall evaluation of the differences between the treatments in the trial. We propose that the combined response to treatment (CRT) be used as this overall measure. The definition and estimation of the CRT can be derived from either a fixed-effects or a random-effects model. For the latter we introduce the ECRT--the expected combined response to treatment. We describe and compare both types of model and express our preference for the random-effects model. We stress that the number of patients enrolled at a centre is a random variable and show that this source of randomness inflates the variance of the estimated ECRT. Variability in enrolment rates over the centres further inflates this variance. A simple conclusion from our results is that if variability in the treatment and centre effects, in the enrolment time, in the number of patients enrolled at a centre and in the enrolment rates is not properly accounted for, then an underpowered trial may result. Using properties of estimators generated by the random-effects model we propose methods for determining the optimal number of centres and total number of patients to enrol in a trial to minimize a loss function that accounts for centre and patient costs and loss of revenue. We discuss variants of the loss function and corresponding optimization problems for different types of enrolment. We end the paper with brief generalizations of the developed techniques to the case where the response is binary.     

Rapra trials corrosion test

EUROPEAN polymer research and testing organization Rapra Technology is increasing the scope of its new product testing by trialling a new corrosion test system.This is a short news story only. Visit www.reinforcedplastics.com for the latest plastics industry news.     

Endpoints in vaccine trials

In this paper we discuss statistical considerations regarding endpoints in preventive vaccine trials. Brief discussion is given to preclinical, Phase I, and Phase II trials, with the bulk of attention paid to endpoint choice and analysis in Phase III efficacy trials. In addition to traditional efficacy measures of vaccine effects for immunized individuals, consideration is given to waning, strain specific efficacy, correlates of protective immunity, postinfection endpoints, and cluster randomized trials.