Analysis of Group Randomized Trials with Multiple Binary Endpoints and Small Number of Groups

The group randomized trial (GRT) is a common study design to assess the effect of an intervention program aimed at health promotion or disease prevention. In GRTs, groups rather than individuals are randomized into intervention or control arms. Then, responses are measured on individuals within those groups. A number of analytical problems beset GRT designs. The major problem emerges from the likely positive intraclass correlation among observations of individuals within a group. This paper provides an overview of the analytical method for GRT data and applies this method to a randomized cancer prevention trial, where multiple binary primary endpoints were obtained. We develop an index of extra variability to investigate group-specific effects on response. The purpose of the index is to understand the influence of individual groups on evaluating the intervention effect, especially, when a GRT study involves a small number of groups. The multiple endpoints from the GRT design are analyzed using a generalized linear mixed model and the stepdown Bonferroni method of Holm.     

Maximum likelihood estimation of generalized linear models for adaptive designs: Applications and asymptotics

Due to increasing discoveries of biomarkers and observed diversity among patients, there is growing interest in personalized medicine for the purpose of increasing the well‐being of patients (ethics) and extending human life. In fact, these biomarkers and observed heterogeneity among patients are useful covariates that can be used to achieve the ethical goals of clinical trials and improving the efficiency of statistical inference. Covariate‐adjusted response‐adaptive (CARA) design was developed to use information in such covariates in randomization to maximize the well‐being of participating patients as well as increase the efficiency of statistical inference at the end of a clinical trial. In this paper, we establish conditions for consistency and asymptotic normality of maximum likelihood (ML) estimators of generalized linear models (GLM) for a general class of adaptive designs. We prove that the ML estimators are consistent and asymptotically follow a multivariate Gaussian distribution. The efficiency of the estimators and the performance of response‐adaptive (RA), CARA, and completely randomized (CR) designs are examined based on the well‐being of patients under a logit model with categorical covariates. Results from our simulation studies and application to data from a clinical trial on stroke prevention in atrial fibrillation (SPAF) show that RA designs lead to ethically desirable outcomes as well as higher statistical efficiency compared to CARA designs if there is no treatment by covariate interaction in an ideal model. CARA designs were however more ethical than RA designs when there was significant interaction.     

A Statistical Perspective on Prevention Trials: A View from the Women’s Health Initiative

Chronic disease prevention trials test strategies to reduce the risk of a specific health event in generally healthy people. These strategies are often thought to affect other health conditions and their use in the population requires a very favorable safety profile. A prevention trial assessing such a strategy is most valuable when designed to capture the overall public health impact and hence provide more comprehensive, reliable information for policy and practice. This broad agenda, and particularly the assessment of multiple outcomes, creates statistical challenges in the design, monitoring, and reporting of such a trial. In this article these issues are described in the context of the Women’s Health Initiative, a large randomized prevention trial testing three interventions in post-menopausal women: hormone therapy, a low-fat diet and calcium and vitamin D supplementation. Each intervention was hypothesized to influence multiple chronic disease rates including cardiovascular disease, stroke, cancers, and fractures. Here the design, monitoring, and reporting of the WHI trials is reviewed in the context of multiple outcomes and the approach to a global assessment of these interventions is described.     

Understanding development and prevention of chronic physical aggression: towards experimental epigenetic studies

The aim of this paper was to highlight how developmental psychopathology, epigenetics and prevention experiments are starting to blend together to explain the developmental causes of chronic physical aggression (CPA) and, more importantly, to help prevent CPA and its associated physical, mental and social problems. After defining the keywords (prevention, chronic and physical aggression), a selected review of published studies is used to answer the following four questions: when should we attempt to prevent onset of CPA? What are the risk factors for CPA? Have early childhood interventions been shown to prevent CPA? Can early preventive interventions benefit from epigenetic studies? The last section of this paper gives two examples of experimental prevention designs that integrate present knowledge of CPA development, risk factors, early childhood preventive interventions and epigenetic programming of brain development during pregnancy and early childhood. I conclude that randomized control trials of preventive interventions during pregnancy and early childhood with a specific focus on epigenetic effects are the research design most likely to advance our understanding of the biopsychosocial mechanisms that lead to CPA, and the only research design that can identify effective interventions for preventing the development of CPA.     

Augmented p-rep designs

Early generation variety trials are very important in plant and tree breeding programs. Typically many entries are tested, often with very little resources available. Unreplicated trials using control plots are popular and it is common to repeat the trials at a number of locations. An alternative is to use p-rep designs, where a proportion of the test entries are replicated at each location; this can obviate the need for control plots. α-Designs are commonly used for replicated variety trials and we show how these can be adapted to produce efficient p-rep designs.     

Statins in prevention and treatment of ischemic stroke

Based on the published data, including the results of large-scale, randomized, placebo-controlled trials, the article presents current strategies for the use of statins in primary and secondary prevention of ischemic stroke. Special attention is paid to the efficacy and advanced applications of statins in acute stroke. Based on the gross data, recommendations for the use of statins in prevention and treatment of ischemic stroke are presented.     

Optimal designs for evaluating a series of treatments

Several articles in this journal have studied optimal designs for testing a series of treatments to identify promising ones for further study. These designs formulate testing as an ongoing process until a promising treatment is identified. This formulation is considered to be more realistic but substantially increases the computational complexity. In this article, we show that these new designs, which control the error rates for a series of treatments, can be reformulated as conventional designs that control the error rates for each individual treatment. This reformulation leads to a more meaningful interpretation of the error rates and hence easier specification of the error rates in practice. The reformulation also allows us to use conventional designs from published tables or standard computer programs to design trials for a series of treatments. We illustrate these using a study in soft tissue sarcoma.     

Bayesian adaptive biased-coin designs for clinical trials with normal responses

Adaptive designs are used in phase III clinical trials for skewing the allocation pattern toward the better treatments. We use optimum design theory to derive a skewed Bayesian biased-coin procedure for sequential designs with continuous responses. The skewed designs are used to provide adaptive designs, the performance of which is studied numerically and theoretically. Important properties are loss and the proportion of allocation to the better treatment.     

Robust inference for the stepped wedge design

Stepped wedge designed trials are a type of cluster-randomized study in which the intervention is introduced to each cluster in a random order over time. This design is often used to assess the effect of a new intervention as it is rolled out across a series of clinics or communities. Based on a permutation argument, we derive a closed-form expression for an estimate of the intervention effect, along with its standard error, for a stepped wedge design trial. We show that these estimates are robust to misspecification of both the mean and covariance structure of the underlying data-generating mechanism, thereby providing a robust approach to inference for the intervention effect in stepped wedge designs. We use simulations to evaluate the type 1 error and power of the proposed estimate and to compare the performance of the proposed estimate to the optimal estimate when the correct model specification is known. The limitations, possible extensions, and open problems regarding the method are discussed.     

Intervenciones para reducir los riesgos multifactoriales de caídas

This article provides an overview of common intervention strategies used to prevent falls and fall-related injuries in older people. Fall incidence increases with age and causes a tremendous amount of morbidity, mortality, and use of healthcare services. Major risk factors for falling are diverse, and many of them —such as balance impairment, unsteady gait, muscle weakness, drug side effects, and environmental hazards— are potentially modifiable. Medical assessment of fall risks and provision of appropriate interventions is challenging due to the complex nature of falls. Consensus panels of experts have developed evidence-based practice guidelines for fall prevention and management. Numerous fall prevention strategies have been studied, and there is considerable evidence to suggest that certain types of fall prevention strategies are more effective than others. Findings from individual studies have been substantiated by careful meta-analysis of large numbers of controlled clinical trials. These meta-analyses have concluded that the most effective (and cost-effective) fall reduction programs involve systematic fall risk assessment and targeted interventions, exercise programs, and environmental inspection and hazard reduction programs. One large recent meta-analysis showed that interventions using multidimensional risk assessment and risk reduction lowered the risk of falling by 18%, while exercise reduced the risk of falls by 12%. Home modification was effective when incorporated into a multi-factorial intervention, targeted to fall-prone individuals. These findings indicate that the most promising approaches to fall prevention will involve interdisciplinary collaboration in assessment and interventions.     

FACTORS INFLUENCING THE EFFICIENCY OF INCOMPLETE BLOCK DESIGNS IN SENSORY EVALUATION EXPERIMENTS

The efficiencies of incomplete block designs were investigated by comparing two hundred and twenty eight analyses from eleven trials using hedonic scales with corresponding randomized complete block analyses. Of the ten explanatory factors examined, only the panelist, the product type, the number of samples per session and the average score of the data had an effect on the efficiency of incomplete block designs. The effect of product type was attributed to influences of produce consumed outside the trial, and the effect of the data mean reflected decreased conscientiousness with products the panelists disliked. With three and four samples per session, incomplete block designs were 31 % and 2 % more efficient, respectively, than randomized complete block designs. When five or more samples were tested, the incomplete block designs were markedly less efficient. The practical implications of all these effects on experimental design are discussed.     

Childhood Obesity Prevention: An Intervention Targeting Primary Caregivers of School Children

Community‐based participatory research (CBPR) was used to design and evaluate the effectiveness of a culturally relevant, science‐based intervention for the prevention of childhood obesity in the Commonwealth of the Northern Mariana Islands (CNMI), a US Commonwealth in the western Pacific. This cognitive behavioral lifestyle intervention, Project Familia Giya Marianas (PFGM), was offered during the 2005–2007 school years in all CNMI public elementary schools over eight sessions to primary caregivers of 3rd grade children (N = 407). A crossover design was utilized with half of the schools offering the intervention in the Fall term, while the other half delivered the sessions in the Spring term. The primary outcome measure was change in BMI z‐score. There was an intervention‐dependent effect on BMI z‐score, with program impact being a function of baseline BMI and the number of lessons attended. This effect was most apparent in students whose baseline BMI z‐score was in healthy range (≥5 to <85 percentile). In both Asian and Pacific Island groups, children whose caregivers completed 5–8 lessons experienced a significant change in BMI z‐score as compared to those with 0 lessons (P < 0.05). Research that integrates multidisciplinary and multimethod approaches is effective in identifying and/or devising solutions to address a complex condition such as childhood obesity. PFGM demonstrated that community participation can be successfully utilized in the development and implementation of childhood obesity prevention programs.     

Lifestyle Interventions Limit Gestational Weight Gain in Women with Overweight or Obesity: LIFE‐Moms Prospective Meta‐Analysis

Objective

This study aimed to evaluate the effects of varied lifestyle intervention programs designed to ameliorate excess gestational weight gain (GWG) in pregnant women with overweight or obesity compared with standard care, including effects on pregnancy outcomes.

Methods

Seven clinical centers conducted separate randomized clinical trials to test different lifestyle intervention strategies to modify GWG in diverse populations. Eligibility criteria, specific outcome measures, and assessment procedures were standardized across trials. The results of the separate trials were combined using an individual‐participant data meta‐analysis.

Results

For the 1,150 women randomized, the percent with excess GWG per week was significantly lower in the intervention group compared with the standard care group (61.8% vs. 75.0%; odds ratio [95% CI]: 0.52 [0.40 to 0.67]). Total GWG from enrollment to 36 weeks' gestation was also lower in the intervention group (8.1 ± 5.2 vs. 9.7 ± 5.4 kg; mean difference: ?1.59 kg [95% CI:?2.18 to ?0.99 kg]). The results from the individual trials were similar. The intervention and standard care groups did not differ in preeclampsia, gestational diabetes, cesarean delivery, or birth weight.

Conclusions

Behavioral lifestyle interventions focusing primarily on diet and physical activity among women with overweight and obesity resulted in a significantly lower proportion of women with excess GWG. This modest beneficial effect was consistent across diverse intervention modalities in a large, racially and socioeconomically diverse US population of pregnant women.

     

School-Based Internet Obesity Prevention Programs for Adolescents: A Systematic Literature Review

In response to the childhood obesity epidemic, numerous studies on school-based Internet obesity prevention interventions have been conducted. The purpose of this systematic review is to describe, synthesize, and evaluate the research on school-based Internet obesity prevention programs for adolescents. Medline, CINAHL, and PsycInfo were searched from January 1995 to August 2012 to locate relevant studies. Ninety-one reports were initially identified, with 12 meeting the inclusion criteria. Studies had variable control groups, program content, and sample characteristics. Though few authors reported on implementation processes or body mass index (BMI) outcomes, the majority of studies were effective in improving health behaviors in the short term. Most studies were judged to have a high or unclear risk of bias in at least two domains, thus the quality of evidence for this body of literature is moderate. Further research is needed to examine programs of longer duration, optimal dose and timing of programs, cost-effectiveness, and mediators and moderators of intervention outcomes.     

Using Multiple Types of Studies in Systematic Reviews of Health Care Interventions – A Systematic Review

Background

A systematic review may evaluate different aspects of a health care intervention. To accommodate the evaluation of various research questions, the inclusion of more than one study design may be necessary. One aim of this study is to find and describe articles on methodological issues concerning the incorporation of multiple types of study designs in systematic reviews on health care interventions. Another aim is to evaluate methods studies that have assessed whether reported effects differ by study types.

Methods and Findings

We searched PubMed, the Cochrane Database of Systematic Reviews, and the Cochrane Methodology Register on 31 March 2012 and identified 42 articles that reported on the integration of single or multiple study designs in systematic reviews. We summarized the contents of the articles qualitatively and assessed theoretical and empirical evidence. We found that many examples of reviews incorporating multiple types of studies exist and that every study design can serve a specific purpose. The clinical questions of a systematic review determine the types of design that are necessary or sufficient to provide the best possible answers. In a second independent search, we identified 49 studies, 31 systematic reviews and 18 trials that compared the effect sizes between randomized and nonrandomized controlled trials, which were statistically different in 35%, and not different in 53%. Twelve percent of studies reported both, different and non-different effect sizes.

Conclusions

Different study designs addressing the same question yielded varying results, with differences in about half of all examples. The risk of presenting uncertain results without knowing for sure the direction and magnitude of the effect holds true for both nonrandomized and randomized controlled trials. The integration of multiple study designs in systematic reviews is required if patients should be informed on the many facets of patient relevant issues of health care interventions.     

Relation of Food Intake Behaviors and Obesity Development in Young Common Marmoset Monkeys

Objective : Increasing prevalence of childhood obesity and associated risks of adult type disease have led to worldwide concern. It remains unclear how genetic predisposition, environmental exposure to obesogenic food, and developmental programming interact to lead to overweight and obese children. The development of a nonhuman primate model of obesity, and particularly juvenile obesity, is an important step to elucidating the factors associated with obesity and evaluating intervention strategies. Design and Methods : Infant marmosets were followed from birth to 12 months of age. Feeding phenotypes were determined through the use of behavioral observation, solid food intake trials, and liquid feeding trials monitored via lickometer. Results : Marmosets found to be obese at 12 months of age (more than 14%body fat) start consuming solid food sooner and initiate more time off of care givers. These individuals developed stable feeding phenotypes that included being more efficient consumers during liquid intake trials, drinking more grams of diet per contact with the licksit. Conclusions : The weaning process appears to be particularly important in the development of feeding phenotypes and the development of juvenile obesity for the marmosets, and thus this is the time that should be focused upon for intervention testing in both nonhuman primates and children.     

Effectiveness of a Randomized Controlled Lifestyle Intervention to Prevent Obesity among Chinese Primary School Students: CLICK-Obesity Study

Background

Childhood obesity has been increasing rapidly worldwide. There is limited evidence for effective lifestyle interventions to prevent childhood obesity worldwide, especially in developing countries like China. The objective of this study was to assess the effectiveness of a school-based multi-component lifestyle childhood obesity prevention program (the CLICK-Obesity study) in Mainland China.

Methods

A cluster randomized controlled trial was developed among grade 4 students from 8 urban primary schools (638 students in intervention, 544 as control) in Nanjing City, China. Students were randomly allocated to the control or intervention group at school-level. A one-year multi-component intervention program (classroom curriculum, school environment support, family involvement and fun programs/events) together with routine health education was provided to the intervention group, while the control group received routine health education only. The main outcome variables assessed were changes in body mass index, obesity occurrence, obesity-related lifestyle behaviors and knowledge.

Results

Overall, 1108 (93.7%) of the 1182 enrolled students completed the intervention study. The intervention group had a larger marginal reduction than did the control group in overall mean BMI value (-0.32±1.36 vs. -0.29±1.40, p = 0.09), although this was not significant. Compared with the control group, the intervention group was more likely to decrease their BMI (OR = 1.44, 95%CI = 1.10, 1.87) by 0.5 kg/m² or above, increase the frequency of jogging/running (OR = 1.55, 95%CI = 1.18, 2.02), decrease the frequency of TV/computer use (OR = 1.41, 95%CI = 1.09, 1.84) and of red meat consumption (OR = 1.50, 95%CI = 1.15, 1.95), change commuting mode to/from school from sedentary to active mode (OR = 2.24, 95%CI = 1.47, 3.40), and be aware of the harm of selected obesity risk factors.

Conclusions

The school-based lifestyle intervention program was practical and effective in improving health behaviors and obesity-related knowledge for children in China. This study provides important policy implications on school-based intervention programs for modifications of obesity-related lifestyles.

Trial Registration

Chinese Clinical Trial Registry ChiCTR-ERC-11001819