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Group-randomized trials are randomized studies that allocate intact groups of individuals to different comparison arms. A frequent practical limitation to adopting such research designs is that only a limited number of groups may be available, and therefore, simple randomization is unable to adequately balance multiple group-level covariates between arms. Therefore, covariate-based constrained randomization was proposed as an allocation technique to achieve balance. Constrained randomization involves generating a large number of possible allocation schemes, calculating a balance score that assesses covariate imbalance, limiting the randomization space to a prespecified percentage of candidate allocations, and randomly selecting one scheme to implement. When the outcome is binary, a number of statistical issues arise regarding the potential advantages of such designs in making inference. In particular, properties found for continuous outcomes may not directly apply, and additional variations on statistical tests are available. Motivated by two recent trials, we conduct a series of Monte Carlo simulations to evaluate the statistical properties of model-based and randomization-based tests under both simple and constrained randomization designs, with varying degrees of analysis-based covariate adjustment. Our results indicate that constrained randomization improves the power of the linearization F-test, the KC-corrected GEE t-test (Kauermann and Carroll, 2001, Journal of the American Statistical Association 96, 1387-1396), and two permutation tests when the prognostic group-level variables are controlled for in the analysis and the size of randomization space is reasonably small. We also demonstrate that constrained randomization reduces power loss from redundant analysis-based adjustment for non-prognostic covariates. Design considerations such as the choice of the balance metric and the size of randomization space are discussed. [ABSTRACT FROM AUTHOR]

This study aimed to find the set of risk indicators best able to predict root caries (RC) incidence in caries-active adults utilizing data from the Xylitol for Adult Caries Trial (X-ACT). Five logistic regression models were compared with respect to their predictive performance for incident RC using data from placebo-control participants with exposed root surfaces at baseline and from two study centers with ancillary data collection (n = 155). Prediction performance was assessed from baseline variables and after including ancillary variables [smoking, diet, use of removable partial dentures (RPD), toothbrush use, income, education, and dental insurance]. A sensitivity analysis added treatment to the models for both the control and treatment participants (n = 301) to predict RC for the control participants. Forty-nine percent of the control participants had incident RC. The model including the number of follow-up years at risk, the number of root surfaces at risk, RC index, gender, race, age, and smoking resulted in the best prediction performance, having the highest AUC and lowest Brier score. The sensitivity analysis supported the primary analysis and gave slightly better performance summary measures. The set of risk indicators best able to predict RC incidence included an increased number of root surfaces at risk and increased RC index at baseline, followed by white race and nonsmoking, which were strong nonsignificant predictors. Gender, age, and increased number of follow-up years at risk, while included in the model, were also not statistically significant. The inclusion of health, diet, RPD use, toothbrush use, income, education, and dental insurance variables did not improve the prediction performance. [ABSTRACT FROM AUTHOR]

Context: Pragmatic trials lack the relatively tight quality control of traditional efficacy studies and hence may pose added analytic challenges owing to the practical realities faced in carrying them out. Case Description: STOP CRC is a cluster randomized trial testing the effectiveness of automated, electronic medical record (EMR)-driven strategies to raise colorectal cancer (CRC) screening rates in safety net clinics. Screen-eligible participants were accrued during year 1 and followed for 12 months (measurement window) to assess completion of a fecal screening test. Control clinics implemented the intervention in year 2. Implementation Challenges/Analytic Issues: Due to limitations on how we could build the intervention tools, the overlap of the year 1 measurement windows with year 2 intervention rollout posed a potential for contamination of the primary outcome for control participants. In addition, a variety of factors led to a lack of synchronization of the measurement windows with actual intervention delivery. In both cases, the net impact of these factors would be to diminish the estimated impact of the intervention. Proposed Solutions: We dealt with the overlap issue by delaying the start of intervention rollout to control clinics in year 2 by 6 months and by truncating the measurement windows for intervention and control participants at this point. In addition we formulated three sensitivity analyses to help address the issue of asynchronization. Conclusion: This case study might help other investigators facing similar challenges think about such issues and the pros and cons of various strategies for dealing with them. [ABSTRACT FROM AUTHOR]

Background Colorectal cancer is the second-leading cause of cancer deaths in the United States. The Strategies and Opportunities to Stop Colorectal Cancer (STOP CRC) in Priority Populations study is a pragmatic trial and a collaboration between two research institutions and a network of more than 200 safety net clinics. The study will assess the effectiveness of a system-based intervention designed to improve the rates of colorectal-cancer screening using fecal immunochemical testing (FIT) in federally qualified health centers in Oregon and Northern California. Material and methods STOP CRC is a cluster-randomized comparative-effectiveness pragmatic trial enrolling 26 clinics. Clinics will be randomized to one of two arms. Clinics in the intervention arm (1) will use an automated, data-driven, electronic health record-embedded program to identify patients due for colorectal screening and mail FIT kits (with pictographic instructions) to them; (2) will conduct an improvement process (e.g. Plan-Do-Study-Act) to enhance the adoption, reach, and effectiveness of the program. Clinics in the control arm will provide opportunistic colorectal-cancer screening to patients at clinic visits. The primary outcomes are: proportion of age- and screening-eligible patients completing a FIT within 12 months; and cost, cost-effectiveness, and return on investment of the intervention. Conclusions This large-scale pragmatic trial will leverage electronic health record information and existing clinic staff to enroll a broad range of patients, including many with historically low colorectal-cancer screening rates. If successful, the program will provide a model for a cost-effective and scalable method to raise colorectal-cancer screening rates. [ABSTRACT FROM AUTHOR]

Objective: We have previously shown that racial composition of behavioral intervention groups does not affect achieved weight loss. However, it is unclear if the race of the interventionist affects intervention outcomes. The objective of this analysis is to estimate the impact of race concordance between participant and interventionist on weight change in the initial weight loss phase (phase I) of the Weight Loss Maintenance trial (WLM). Design and Methods: A total of 1,685 overweight or obese adults (BMI 25-45 kg/m2) who were taking medication for hypertension and/or dyslipidemia participated in phase I of the WLM trial. All participants received a 6-month intensive behavioral intervention in groups of 15-20 facilitated by a trained interventionist. The main outcome is change in weight at 6 months. Results: Participants were on average 55 years of age, 67% female and 44% African American (AA). Three of seventeen interventionists were AA, 14 were non-AA. Seventy-three percent of participants shared race concordance with the interventionist. There was a small but statistically significant difference in weight change of participants who were the same race as the interventionist (−5.84 kg, s.e. 0.17) as compared with those who were not race concordant (−5.04 kg, s.e. 0.33), a difference of 0.8 kg, ( P = 0.04). The impact of concordance on weight change differed by race (i.e., interaction of race and concordance was significant, P = 0.02). Conclusions: In a post hoc analysis of a group-based behavioral intervention, race concordance for non-AA participants was associated with slightly greater weight loss. Race concordance was not associated with weight loss for AA participants. [ABSTRACT FROM AUTHOR]

Background: Pharmacy databases are commonly used to assess medication usage, and a number of measures have been developed to measure patients' adherence to medication. An extensive literature now supports these measures, although few studies have systematically compared the properties of different adherence measures. Methods: As part of an 18-month randomized clinical trial to assess the impact of automated telephone reminders on adherence to inhaled corticosteroids (ICS) among 6903 adult members of a managed care organization, we computed eight pharmacy-based measures of ICS adherence using outpatient pharmacy dispensing records obtained from the health plan's electronic medical record. We used simple descriptive statistics to compare the relative performance characteristics of these measures. Results: Comparative analysis found a relative upward bias in adherence estimates for those measures that require at least one dispensing event to be calculated. Measurement strategies that require a second dispensing event evidence even greater upward bias. These biases are greatest with shorter observation times. Furthermore, requiring a dispensing to be calculated meant that these measures could not be defined for large numbers of individuals (17-32 % of participants in this study). Measurement strategies that do not require a dispensing event to be calculated appear least vulnerable to these biases and can be calculated for everyone. However they do require additional assumptions and data (e.g., pre-intervention dispensing data) to support their validity. Conclusions: Many adherence measures require one, or sometimes two, dispensings in order to be defined. Since such measures assume all dispensed medication is used as directed, they have a built in upward bias that is especially pronounced when they are calculated over relatively short timeframes (< 9 months). Less biased measurement strategies that do not require a dispensing event are available, but require additional data to support their validity. Trial registration: The study was funded by grant R01HL83433 from the National Heart, Lung and Blood Institute (NHLBI) and is filed as study NCT00414817 in the clinicaltrials.gov database. [ABSTRACT FROM AUTHOR]

Objectives: This report describes the training of dental examiners participating in two dental caries clinical trials and reports the inter- and intra-examiner reliability scores from the initial standardization sessions. Methods: Study examiners were trained to use a modified International Caries Detection and Assessment System II system to detect the visual signs of non-cavitated and cavitated dental caries in adult subjects. Dental caries was classified as no caries (S), non-cavitated caries (D1), enamel caries (D2), and dentine caries (D3). Three standardization sessions involving 60 subjects and 3,604 tooth surface calls were used to calculate several measures of examiner reliability. Results: The prevalence of dental caries observed in the standardization sessions ranged from 1.4 percent to 13.5 percent of the coronal tooth surfaces examined. Overall agreement between pairs of examiners ranged from 0.88 to 0.99. An intra-class coefficient threshold of 0.60 was surpassed for all but one examiner. Inter-examiner unweighted kappa values were low (0.23-0.35), but weighted kappas and the ratio of observed to maximum kappas were more encouraging (0.42-0.83). The highest kappa values occurred for the S/D1 versus D2/D3 two-level classification of dental caries, for which seven of the eight examiners achieved observed to maximum kappa values over 0.90. Intra-examiner reliability was notably higher than inter-examiner reliability for all measures and dental caries classifications employed. Conclusion: The methods and results for the initial examiner training and standardization sessions for two large clinical trials are reported. Recommendations for others planning examiner training and standardization sessions are offered. [ABSTRACT FROM AUTHOR]

Background: Dental caries is one of the primary causes of tooth loss among adults. It is estimated to affect a majority of Americans aged 55 and older, with a disproportionately higher burden in disadvantaged populations. Although a number of treatments are currently in use for caries prevention in adults, evidence for their efficacy and effectiveness is limited. Methods/Design: The Prevention of Adult Caries Study (PACS) is a multicenter, placebo-controlled, double-blind, randomized clinical trial of the efficacy of a chlorhexidine (10% w/v) dental coating in preventing adult caries. Participants (n = 983) were recruited from four different dental delivery systems serving four diverse communities, including one American Indian population, and were randomized to receive either chlorhexidine or a placebo treatment. The primary outcome is the net caries increment (including non-cavitated lesions) from baseline to 13 months of follow-up. A cost-effectiveness analysis also will be considered. Discussion: This new dental treatment, if efficacious and approved for use by the Food and Drug Administration (FDA), would become a new in-office, anti-microbial agent for the prevention of adult caries in the United States. Trial Registration Number: NCT00357877. [ABSTRACT FROM AUTHOR]

Background: Dental caries incidence in adults is similar to that in children and adolescents, but few caries preventive agents have been evaluated for effectiveness in adults populations. In addition, dentists direct fewer preventive services to their adult patients. Xylitol, an over-the-counter sweetener, has shown some potential as a caries preventive agent, but the evidence for its effectiveness is not yet conclusive and is based largely on studies in child populations. Methods/Design: X-ACT is a three-year, multi-center, placebo controlled, double-blind, randomized clinical trial that tests the effects of daily use of xylitol lozenges versus placebo lozenges on the prevention of adult caries. The trial has randomized 691 participants (ages 21-80) to the two arms. The primary outcome is the increment of cavitated lesions. Discussion: This trial should help resolve the overall issue of the effectiveness of xylitol in preventing caries by contributing evidence with a low risk of bias. Just as importantly, the trial will provide much-needed information about the effectiveness of a promising caries prevention agent in adults. An effective xylitol-based caries prevention intervention would represent an easily disseminated method to extend caries prevention to individuals not receiving caries preventive treatment in the dental office. Trial Registration: ClinicalTrials.Gov NCT00393055. [ABSTRACT FROM AUTHOR]

The article provides information on the Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER) randomized clinical trial. A total of 810 healthy adults with prehypertension participated in the study in which they were randomly divided into three groups. Based on the results, the researchers concluded that lifestyle changes can be achieved and continued over 18 months which can lead to improved hypertension control.

Background. Weight is typically measured on a single day in research studies. This practice assumes negligible day-to-day weight variability, although little evidence exists to support this assumption. We compared the precision of measuring weight on one versus two days among control participants in the Weight Loss Maintenance trial. Methods. Trained staff measured weight on two separate days at baseline, 12 months, and 30 months (2004-2007). We calculated the standard deviation (SD) of mean weight change from baseline to the 12- and 30-month visits using (a) the first and (b) both daily weights from each visit and conducted a variance components analysis (2009). Results. Of the 316 participants with follow-up measurements, mean (SD) age was 55.8 (8.5) years, BMI was 30.8 (4.5) kg/m2, 64% were women, 36% were black, and 50% were obese. At 12 months, the SD of mean weight change was 5.1 versus 5.0 kg using one versus two days of weight measurements (P = .76), while at 30 months the corresponding SDs were 6.3 and 6.3 kg (P = .98). We observed similar findings within subgroups of BMI, sex, and race. Day-to-day variability within individuals accounted for <1% of variability in weight. Conclusions. Measurement of weight on two separate days has no advantage over measurement on a single day in studies with well-standardized weight measurement protocols. [ABSTRACT FROM AUTHOR]

PURPOSE: To describe PREMIER, a randomized trial to determine the effects of multi-component lifestyle interventions on blood pressure (BP).METHODS: Participants with above optimal BP through stage 1 hypertension were randomized to: 1) a behavioral lifestyle (BLS) intervention that implements established recommendations, 2) a BLS intervention that implements established recommendations plus the DASH diet, or 3) an advice only standard of care group. The two BLS interventions consist of group and individual counseling sessions for 18 months. The primary outcome is systolic BP at 6 months. Additional outcomes include diastolic BP and homocysteine at 6 months; systolic and diastolic BP at 18 months; fasting lipids, glucose and insulin at 6 and 18 months; and effects in subgroup.CONCLUSION: Results from the PREMIER trial will provide scientific rationale for implementing multi-component behavioral lifestyle intervention programs to control BP and prevent CVD. [Copyright &y& Elsevier]

Background: The effect of dietary composition on blood pressure is a subject of public health importance. We studied the effect of different levels of dietary sodium, in conjunction with the Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in vegetables, fruits, and low-fat dairy products, in persons with and in those without hypertension. Methods: A total of 412 participants were randomly assigned to eat either a control diet typical of intake in the United States or the DASH diet. Within the assigned diet, participants ate foods with high, intermediate, and low levels of sodium for 30 consecutive days each, in random order. Results: Reducing the sodium intake from the high to the intermediate level reduced the systolic blood pressure by 2.1 mm Hg (P<0.001) during the control diet and by 1.3 mm Hg (P=0.03) during the DASH diet. Reducing the sodium intake from the intermediate to the low level caused additional reductions of 4.6 mm Hg during the control diet (P<0.001) and 1.7 mm Hg during the DASH diet (P<0.01). The effects of sodium were observed in participants with and in those without hypertension, blacks and those of other races, and women and men. The DASH diet was associated with a significantly lower systolic blood pressure at each sodium level; and the difference was greater with high sodium levels than with low ones. As compared with the control diet with a high sodium level, the DASH diet with a low sodium level led to a mean systolic blood pressure that was 7.1 mm Hg lower in participants without hypertension, and 11.5 mm Hg lower in participants with hypertension. Conclusions: The reduction of sodium intake to levels below the current recommendation of 100 mmol per day and the DASH diet both lower blood pressure substantially, with greater effects in combination than singly. Long-term health benefits will depend on the ability of people to make long-lasting dietary changes and the increased availability of lower-sodium foods. (N Engl J Med 2001;344:3-10.) [ABSTRACT FROM AUTHOR]