Evaluating tests for cluster-randomized trials with few clusters under generalized linear mixed models with covariate adjustment: A simulation study.

Generalized linear mixed models (GLMM) are commonly used to analyze clustered data, but when the number of clusters is small to moderate, standard statistical tests may produce elevated type I error rates. Small-sample corrections have been proposed for continuous or binary outcomes without covariate adjustment. However, appropriate tests to use for count outcomes or under covariate-adjusted models remains unknown. An important setting in which this issue arises is in cluster-randomized trials (CRTs). Because many CRTs have just a few clusters (eg, clinics or health systems), covariate adjustment is particularly critical to address potential chance imbalance and/or low power (eg, adjustment following stratified randomization or for the baseline value of the outcome). We conducted simulations to evaluate GLMM-based tests of the treatment effect that account for the small (10) or moderate (20) number of clusters under a parallel-group CRT setting across scenarios of covariate adjustment (including adjustment for one or more person-level or cluster-level covariates) for both binary and count outcomes. We find that when the intraclass correlation is non-negligible ( ≥ $$ \ge $$ 0.01) and the number of covariates is small ( ≤ $$ \le $$ 2), likelihood ratio tests with a between-within denominator degree of freedom have type I error rates close to the nominal level. When the number of covariates is moderate ( ≥ $$ \ge $$ 5), across our simulation scenarios, the relative performance of the tests varied considerably and no method performed uniformly well. Therefore, we recommend adjusting for no more than a few covariates and using likelihood ratio tests with a between-within denominator degree of freedom.

Evaluating analytic models for individually randomized group treatment trials with complex clustering in nested and crossed designs.

Many individually randomized group treatment (IRGT) trials randomly assign individuals to study arms but deliver treatments via shared agents, such as therapists, surgeons, or trainers. Post-randomization interactions induce correlations in outcome measures between participants sharing the same agent. Agents can be nested in or crossed with trial arm, and participants may interact with a single agent or with multiple agents. These complications have led to ambiguity in choice of models but there have been no systematic efforts to identify appropriate analytic models for these study designs. To address this gap, we undertook a simulation study to examine the performance of candidate analytic models in the presence of complex clustering arising from multiple membership, single membership, and single agent settings, in both nested and crossed designs and for a continuous outcome. With nested designs, substantial type I error rate inflation was observed when analytic models did not account for multiple membership and when analytic model weights characterizing the association with multiple agents did not match the data generating mechanism. Conversely, analytic models for crossed designs generally maintained nominal type I error rates unless there was notable imbalance in the number of participants that interact with each agent.

Active Postlicensure Safety Surveillance for Recombinant Zoster Vaccine Using Electronic Health Record Data.

Recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Brentford, United Kingdom) is an adjuvanted glycoprotein vaccine that was licensed in 2017 to prevent herpes zoster (shingles) and its complications in older adults. In this prospective, postlicensure Vaccine Safety Datalink study using electronic health records, we sequentially monitored a real-world population of adults aged ≥50 years who received care in multiple US Vaccine Safety Datalink health systems to identify potentially increased risks of 10 prespecified health outcomes, including stroke, anaphylaxis, and Guillain-Barré syndrome (GBS). Among 647,833 RZV doses administered from January 2018 through December 2019, we did not detect a sustained increased risk of any monitored outcome for RZV recipients relative to either historical (2013-2017) recipients of zoster vaccine live, a live attenuated virus vaccine (Zostavax; Merck & Co., Inc., Kenilworth, New Jersey), or contemporary non-RZV vaccine recipients who had an annual well-person visit during the 2018-2019 study period. We confirmed prelicensure trial findings of increased risks of systemic and local reactions following RZV. Our study provides additional reassurance about the overall safety of RZV. Despite a large sample, uncertainty remains regarding potential associations with GBS due to the limited number of confirmed GBS cases that were observed.

Preoperative Depression Status and 5 Year Metabolic and Bariatric Surgery Outcomes in the PCORnet Bariatric Study Cohort.

OBJECTIVE: To examine whether depression status before metabolic and bariatric surgery (MBS) influenced 5-year weight loss, diabetes, and safety/utilization outcomes in the PCORnet Bariatric Study. SUMMARY OF BACKGROUND DATA: Research on the impact of depression on MBS outcomes is inconsistent with few large, long-term studies. METHODS: Data were extracted from 23 health systems on 36,871 patients who underwent sleeve gastrectomy (SG; n=16,158) or gastric bypass (RYGB; n=20,713) from 2005-2015. Patients with and without a depression diagnosis in the year before MBS were evaluated for % total weight loss (%TWL), diabetes outcomes, and postsurgical safety/utilization (reoperations, revisions, endoscopy, hospitalizations, mortality) at 1, 3, and 5 years after MBS. RESULTS: 27.1% of SG and 33.0% of RYGB patients had preoperative depression, and they had more medical and psychiatric comorbidities than those without depression. At 5 years of follow-up, those with depression, versus those without depression, had slightly less %TWL after RYGB, but not after SG (between group difference = 0.42%TWL, P = 0.04). However, patients with depression had slightly larger HbA1c improvements after RYGB but not after SG (between group difference = - 0.19, P = 0.04). Baseline depression did not moderate diabetes remission or relapse, reoperations, revision, or mortality across operations; however, baseline depression did moderate the risk of endoscopy and repeat hospitalization across RYGB versus SG. CONCLUSIONS: Patients with depression undergoing RYGB and SG had similar weight loss, diabetes, and safety/utilization outcomes to those without depression. The effects of depression were clinically small compared to the choice of operation.

Acceptability and Adherence to Home, Kiosk, and Clinic Blood Pressure Measurement Compared to 24-H Ambulatory Monitoring.

BACKGROUND: The US Preventive Services Task Force recommends measuring blood pressure (BP) outside of clinic/office settings. While various options are available, including home devices, BP kiosks, and 24-h ambulatory BP monitoring (ABPM), understanding patient acceptability and adherence is a critical factor for implementation. OBJECTIVE: To compare the acceptability and adherence of clinic, home, kiosk, and ABPM measurement. DESIGN: Comparative diagnostic accuracy study which randomized adults to one of three BP measurement arms: clinic, home, and kiosk. ABPM was conducted on all participants. PARTICIPANTS: Adults (18-85 years) receiving care at 12 Kaiser Permanente Washington primary care clinics (Washington State, USA) with a high BP (≥ 138 mmHg systolic or ≥ 88 mmHg diastolic) in the electronic health record with no hypertension diagnosis and on no hypertensive medications and with high BP at a research screening visit. MEASURES: Patient acceptability was measured using a validated survey which was used to calculate an overall acceptability score (range 1-7) at baseline, after completing their assigned BP measurement intervention, and after completing ABPM. Adherence was defined based on the pre-specified number of BP measurements completed. KEY RESULTS: Five hundred ten participants were randomized (mean age 59 years), with mean BP of 150/88. Overall acceptability score was highest (i.e. most acceptable) for Home BP (mean 6.2, SD 0.7) and lowest (least acceptable) for ABPM (mean 5.0, SD 1.0); scores were intermediate for Clinic (5.5, SD 1.1) and Kiosk (5.4, SD 1.0). Adherence was higher for Home (154/170, 90.6%) and Clinic (150/172, 87.2%) than for Kiosk (114/168, 67.9%)). The majority of participants (467/510, 91.6%) were adherent to ABPM. CONCLUSIONS: Participants found home BP measurement most acceptable followed by clinic, BP kiosks, and ABPM. Our findings, coupled with recent evidence regarding the accuracy of home BP measurement, further support the routine use of home-based BP measurement in primary care practice in the US. TRIAL REGISTRATION: ClinicalTrials.gov NCT03130257 https://clinicaltrials.gov/ct2/show/NCT03130257.

Considerations for Subgroup Analyses in Cluster-Randomized Trials Based on Aggregated Individual-Level Predictors.

In research assessing the effect of an intervention or exposure, a key secondary objective often involves assessing differential effects of this intervention or exposure in subgroups of interest; this is often referred to as assessing effect modification or heterogeneity of treatment effects (HTE). Observed HTE can have important implications for policy, including intervention strategies (e.g., will some patients benefit more from intervention than others?) and prioritizing resources (e.g., to reduce observed health disparities). Analysis of HTE is well understood in studies where the independent unit is an individual. In contrast, in studies where the independent unit is a cluster (e.g., a hospital or school) and a cluster-level outcome is used in the analysis, it is less well understood how to proceed if the HTE analysis of interest involves an individual-level characteristic (e.g., self-reported race) that must be aggregated at the cluster level. Through simulations, we show that only individual-level models have power to detect HTE by individual-level variables; if outcomes must be defined at the cluster level, then there is often low power to detect HTE by the corresponding aggregated variables. We illustrate the challenges inherent to this type of analysis in a study assessing the effect of an intervention on increasing COVID-19 booster vaccination rates at long-term care centers.

A Centralized Program with Stepped Support Increases Adherence to Colorectal Cancer Screening Over 9 Years: a Randomized Trial.

BACKGROUND: Screening over many years is required to optimize colorectal cancer (CRC) outcomes. OBJECTIVE: To evaluate the effect of a CRC screening intervention on adherence to CRC screening over 9 years. DESIGN: Randomized trial. SETTING: Integrated health care system in Washington state. PARTICIPANTS: Between August 2008 and November 2009, 4653 adults in a Washington state integrated health care system aged 50-74 due for CRC screening were randomized to usual care (UC; N =1163) or UC plus study interventions (interventions: N = 3490). INTERVENTIONS: Years 1 and 2: (arm 1) UC or this plus study interventions; (arm 2) mailed fecal tests or information on scheduling colonoscopy; (arm 3) mailings plus brief telephone assistance; or (arm 4) mailings and assistance plus nurse navigation. In year 3, stepped-intensity participants (arms 2, 3, and 4 combined) still eligible for screening were randomized to either stopped or continued interventions in years 3 and 5-9. MAIN MEASURES: Time in adherence to CRC testing over 9 years (covered time, primary outcome), and percent with no CRC testing in participants assigned to any intervention compared to UC only. Poisson regression models estimated incidence rate ratios for covered time, adjusting for patient characteristics and accounting for variable follow-up time. KEY RESULTS: Compared to UC, intervention participants had 21% more covered time over 9 years (57.5% vs. 69.1%; adjusted incidence rate ratio 1.21, 95% confidence interval 1.16-1.25, P<0.001). Fecal testing accounted for almost all additional covered time among intervention patients. Compared to UC, intervention participants were also more likely to have completed at least one CRC screening test over 9 years or until censorship (88.6% vs. 80.6%, P<0.001). CONCLUSIONS: An outreach program that included mailed fecal tests and phone follow-up led to increased adherence to CRC testing and fewer age-eligible individuals without any CRC testing over 9 years. TRIAL REGISTRATION: Systems of Support (SOS) to Increase Colon Cancer Screening and Follow-up (SOS), NCT00697047, clinicaltrials.gov/ct2/show/NCT00697047.

Clinic, Home, and Kiosk Blood Pressure Measurements for Diagnosing Hypertension: a Randomized Diagnostic Study.

BACKGROUND: The US Preventive Services Task Force recommends blood pressure (BP) measurements using 24-h ambulatory monitoring (ABPM) or home BP monitoring before making a new hypertension diagnosis. OBJECTIVE: Compare clinic-, home-, and kiosk-based BP measurement to ABPM for diagnosing hypertension. DESIGN, SETTING, AND PARTICIPANTS: Diagnostic study in 12 Washington State primary care centers, with participants aged 18-85 years without diagnosed hypertension or prescribed antihypertensive medications, with elevated BP in clinic. INTERVENTIONS: Randomization into one of three diagnostic regimens: (1) clinic (usual care follow-up BPs); (2) home (duplicate BPs twice daily for 5 days); or (3) kiosk (triplicate BPs on 3 days). All participants completed ABPM at 3 weeks. MAIN MEASURES: Primary outcome was difference between ABPM daytime and clinic, home, and kiosk mean systolic BP. Differences in diastolic BP, sensitivity, and specificity were secondary outcomes. KEY RESULTS: Five hundred ten participants (mean age 58.7 years, 80.2% white) with 434 (85.1%) included in primary analyses. Compared to daytime ABPM, adjusted mean differences in systolic BP were clinic (-4.7mmHg [95% confidence interval -7.3, -2.2]; P<.001); home (-0.1mmHg [-1.6, 1.5];P=.92); and kiosk (9.5mmHg [7.5, 11.6];P<.001). Differences for diastolic BP were clinic (-7.2mmHg [-8.8, -5.5]; P<.001); home (-0.4mmHg [-1.4, 0.7];P=.52); and kiosk (5.0mmHg [3.8, 6.2]; P<.001). Sensitivities for clinic, home, and kiosk compared to ABPM were 31.1% (95% confidence interval, 22.9, 40.6), 82.2% (73.8, 88.4), and 96.0% (90.0, 98.5), and specificities 79.5% (64.0, 89.4), 53.3% (38.9, 67.2), and 28.2% (16.4, 44.1), respectively. LIMITATIONS: Single health care organization and limited race/ethnicity representation. CONCLUSIONS: Compared to ABPM, mean BP was significantly lower for clinic, significantly higher for kiosk, and without significant differences for home. Clinic BP measurements had low sensitivity for detecting hypertension. Findings support utility of home BP monitoring for making a new diagnosis of hypertension. TRIAL REGISTRATION: ClinicalTrials.gov NCT03130257 https://clinicaltrials.gov/ct2/show/NCT03130257.

Safety surveillance and the estimation of risk in select populations: Flexible methods to control for confounding while targeting marginal comparisons via standardization.

We consider the critical problem of pharmacosurveillance for adverse events once a drug or medical product is incorporated into routine clinical care. When making inference on comparative safety using large-scale electronic health records, we often encounter an extremely rare binary adverse outcome with a large number of potential confounders. In this context, it is challenging to offer flexible methods to adjust for high-dimensional confounders, whereas use of the propensity score (PS) can help address this challenge by providing both confounding control and dimension reduction. Among PS methods, regression adjustment using the PS as a covariate in an outcome model has been incompletely studied and potentially misused. Previous studies have suggested that simple linear adjustment may not provide sufficient control of confounding. Moreover, no formal representation of the statistical procedure and associated inference has been detailed. In this paper, we characterize a three-step procedure, which performs flexible regression adjustment of the estimated PS followed by standardization to estimate the causal effect in a select population. We also propose a simple variance estimation method for performing inference. Through a realistic simulation mimicking data from the Food and Drugs Administration's Sentinel Initiative comparing the effect of angiotensin-converting enzyme inhibitors and beta blockers on incidence of angioedema, we show that flexible regression on the PS resulted in less bias without loss of efficiency, and can outperform other methods when the PS model is correctly specified. In addition, the direct variance estimation method is a computationally fast and reliable approach for inference.

Challenges and Opportunities for Using Big Health Care Data to Advance Medical Science and Public Health.

Methodological advancements in epidemiology, biostatistics, and data science have strengthened the research world's ability to use data captured from electronic health records (EHRs) to address pressing medical questions, but gaps remain. We describe methods investments that are needed to curate EHR data toward research quality and to integrate complementary data sources when EHR data alone are insufficient for research goals. We highlight new methods and directions for improving the integrity of medical evidence generated from pragmatic trials, observational studies, and predictive modeling. We also discuss needed methods contributions to further ease data sharing across multisite EHR data networks. Throughout, we identify opportunities for training and for bolstering collaboration among subject matter experts, methodologists, practicing clinicians, and health system leaders to help ensure that methods problems are identified and resulting advances are translated into mainstream research practice more quickly.

A Randomized Trial of External Practice Support to Improve Cardiovascular Risk Factors in Primary Care.

PURPOSE: We conducted a randomized controlled trial to compare the effectiveness of adding various forms of enhanced external support to practice facilitation on primary care practices' clinical quality measure (CQM) performance. METHODS: Primary care practices across Washington, Oregon, and Idaho were eligible if they had fewer than 10 full-time clinicians. Practices were randomized to practice facilitation only, practice facilitation and shared learning, practice facilitation and educational outreach visits, or practice facilitation and both shared learning and educational outreach visits. All practices received up to 15 months of support. The primary outcome was the CQM for blood pressure control. Secondary outcomes were CQMs for appropriate aspirin therapy and smoking screening and cessation. Analyses followed an intention-to-treat approach. RESULTS: Of 259 practices recruited, 209 agreed to be randomized. Only 42% of those offered educational outreach visits and 27% offered shared learning participated in these enhanced supports. CQM performance improved within each study arm for all 3 cardiovascular disease CQMs. After adjusting for differences between study arms, CQM improvements in the 3 enhanced practice support arms of the study did not differ significantly from those seen in practices that received practice facilitation alone (omnibus P = .40 for blood pressure CQM). Practices randomized to receive both educational outreach visits and shared learning, however, were more likely to achieve a blood pressure performance goal in 70% of patients compared with those randomized to practice facilitation alone (relative risk = 2.09; 95% CI, 1.16-3.76). CONCLUSIONS: Although we found no significant differences in CQM performance across study arms, the ability of a practice to reach a target level of performance may be enhanced by adding both educational outreach visits and shared learning to practice facilitation.

Improving pragmatic clinical trial design using real-world data.

BACKGROUND: Pragmatic clinical trials often use automated data sources such as electronic health records, claims, or registries to identify eligible individuals and collect outcome information. A specific advantage that this automated data collection often yields is having data on potential participants when design decisions are being made. We outline how this data can be used to inform trial design. METHODS: Our work is motivated by a pragmatic clinical trial evaluating the impact of suicide-prevention outreach interventions on fatal and non-fatal suicide attempts in the 18 months after randomization. We illustrate our recommended approaches for designing pragmatic clinical trials using historical data from the health systems participating in this study. Specifically, we illustrate how electronic health record data can be used to inform the selection of trial eligibility requirements, to estimate the distribution of participant characteristics over the course of the trial, and to conduct power and sample size calculations. RESULTS: Data from 122,873 people with patient health questionnaire (PHQ) responses, recorded in their electronic health records between 1 July 2010 and 31 March 2012, were used to show that the suicide attempt rate in the 18 months following completion of the questionnaire varies by response to item nine of the PHQ. We estimated that the proportion of individuals with a prior recorded elevated PHQ (i.e. history of suicidal ideation) would decrease from approximately 50% at the beginning of a trial to about 5%, 50 weeks later. Using electronic health record data, we conducted simulations to estimate the power to detect a 25% reduction in suicide attempts. Simulation-based power calculations estimated that randomizing 8000 participants per randomization arm would allow 90% power to detect a 25% reduction in the suicide attempt rate in the intervention arm compared to usual care at an alpha rate of 0.05. CONCLUSIONS: Historical data can be used to inform the design of pragmatic clinical trials, a strength of trials that use automated data collection for randomizing participants and assessing outcomes. In particular, realistic sample size calculations can be conducted using real-world data from the health systems in which the trial will be conducted. Data-informed trial design should yield more realistic estimates of statistical power and maximize efficiency of trial recruitment.

A centralized mailed program with stepped increases of support increases time in compliance with colorectal cancer screening guidelines over 5 years: A randomized trial.

BACKGROUND: Screening over many years is required to optimize reductions in colorectal cancer (CRC) mortality. However, no prior trials have compared strategies for obtaining long-term adherence. METHODS: Systems of Support to Increase Colorectal Cancer Screening and Follow-Up was implemented in an integrated health care organization in Washington State. Between 2008 and 2009, 4675 individuals aged 50 to 74 years were randomized to receive the usual care (UC), which included clinic-based strategies to increase CRC screening (arm 1), or, in years 1 and 2, mailings with a call-in number for colonoscopy and mailed fecal tests (arm 2), mailings plus brief telephone assistance (arm 3), or mailings and assistance plus nurse navigation (arm 4). Active-intervention subjects (those in arms 2, 3, and 4 combined) who were still eligible for CRC screening were randomized to mailings being stopped or continued in years 3 and 5. The time in compliance with CRC screening over 5 years was compared for persons assigned to any intervention and persons assigned to UC. Screening tests contributed time on the basis of national guidelines for screening intervals (fecal tests annually, sigmoidoscopy every 5 years, and colonoscopy every 10 years). RESULTS: All participants contributed data, but they were censored at disenrollment, death, the age of 76 years, or a diagnosis of CRC. Compared with UC participants, intervention participants had 31% more adjusted covered time over 5 years (incidence rate ratio, 1.31; 95% confidence interval, 1.25-1.37; covered time, 47.5% vs 62.1%). Fecal testing accounted for almost all additional covered time. CONCLUSIONS: In a health care organization with clinic-based activities to increase CRC screening, a centralized program led to increased CRC screening adherence over 5 years. Longer term data on screening adherence and its impact on CRC outcomes are needed. Cancer 2017;123:4472-80. © 2017 American Cancer Society.

Evaluation of propensity scores, disease risk scores, and regression in confounder adjustment for the safety of emerging treatment with group sequential monitoring.

PURPOSE: The objective of this study was to evaluate regression, matching, and stratification on propensity score (PS) or disease risk score (DRS) in a setting of sequential analyses where statistical hypotheses are tested multiple times. METHODS: In a setting of sequential analyses, we simulated incident users and binary outcomes with different confounding strength, outcome incidence, and the adoption rate of treatment. We compared Type I error rate, empirical power, and time to signal using the following confounder adjustments: (i) regression; (ii) treatment matching (1:1 or 1:4) on PS or DRS; and (iii) stratification on PS or DRS. We estimated PS and DRS using lookwise and cumulative methods (all data up to the current look). We applied these confounder adjustments in examining the association between non-steroidal anti-inflammatory drugs and bleeding. RESULTS: Propensity score and DRS methods had similar empirical power and time to signal. However, DRS methods yielded Type I error rates up to 17% for 1:4 matching and 15.3% for stratification methods when treatment and outcome were common and confounding strength with treatment was stronger. When treatment and outcome were not common, stratification on PS and DRS and regression yielded 8-10% Type I error rates and inflated empirical power. However, when outcome and treatment were common, both regression and stratification on PS outperformed other matching methods with Type I error rates close to 5%. CONCLUSIONS: We suggest regression and stratification on PS when the outcomes and/or treatment is common and use of matching on PS with higher ratios when outcome or treatment is rare or moderately rare.

Statistical lessons learned for designing cluster randomized pragmatic clinical trials from the NIH Health Care Systems Collaboratory Biostatistics and Design Core.

BACKGROUND/AIMS: Pragmatic clinical trials embedded within health care systems provide an important opportunity to evaluate new interventions and treatments. Networks have recently been developed to support practical and efficient studies. Pragmatic trials will lead to improvements in how we deliver health care and promise to more rapidly translate research findings into practice. METHODS: The National Institutes of Health (NIH) Health Care Systems Collaboratory was formed to conduct pragmatic clinical trials and to cultivate collaboration across research areas and disciplines to develop best practices for future studies. Through a two-stage grant process including a pilot phase (UH2) and a main trial phase (UH3), investigators across the Collaboratory had the opportunity to work together to improve all aspects of these trials before they were launched and to address new issues that arose during implementation. Seven Cores were created to address the various considerations, including Electronic Health Records; Phenotypes, Data Standards, and Data Quality; Biostatistics and Design Core; Patient-Reported Outcomes; Health Care Systems Interactions; Regulatory/Ethics; and Stakeholder Engagement. The goal of this article is to summarize the Biostatistics and Design Core's lessons learned during the initial pilot phase with seven pragmatic clinical trials conducted between 2012 and 2014. RESULTS: Methodological issues arose from the five cluster-randomized trials, also called group-randomized trials, including consideration of crossover and stepped wedge designs. We outlined general themes and challenges and proposed solutions from the pilot phase including topics such as study design, unit of randomization, sample size, and statistical analysis. Our findings are applicable to other pragmatic clinical trials conducted within health care systems. CONCLUSION: Pragmatic clinical trials using the UH2/UH3 funding mechanism provide an opportunity to ensure that all relevant design issues have been fully considered in order to reliably and efficiently evaluate new interventions and treatments. The integrity and generalizability of trial results can only be ensured if rigorous designs and appropriate analysis choices are an essential part of their research protocols.

Effect of Mindfulness-Based Stress Reduction vs Cognitive Behavioral Therapy or Usual Care on Back Pain and Functional Limitations in Adults With Chronic Low Back Pain: A Randomized Clinical Trial.

IMPORTANCE: Mindfulness-based stress reduction (MBSR) has not been rigorously evaluated for young and middle-aged adults with chronic low back pain. OBJECTIVE: To evaluate the effectiveness for chronic low back pain of MBSR vs cognitive behavioral therapy (CBT) or usual care. DESIGN, SETTING, AND PARTICIPANTS: Randomized, interviewer-blind, clinical trial in an integrated health care system in Washington State of 342 adults aged 20 to 70 years with chronic low back pain enrolled between September 2012 and April 2014 and randomly assigned to receive MBSR (n = 116), CBT (n = 113), or usual care (n = 113). INTERVENTIONS: CBT (training to change pain-related thoughts and behaviors) and MBSR (training in mindfulness meditation and yoga) were delivered in 8 weekly 2-hour groups. Usual care included whatever care participants received. MAIN OUTCOMES AND MEASURES: Coprimary outcomes were the percentages of participants with clinically meaningful (≥30%) improvement from baseline in functional limitations (modified Roland Disability Questionnaire [RDQ]; range, 0-23) and in self-reported back pain bothersomeness (scale, 0-10) at 26 weeks. Outcomes were also assessed at 4, 8, and 52 weeks. RESULTS: There were 342 randomized participants, the mean (SD) [range] age was 49.3 (12.3) [20-70] years, 224 (65.7%) were women, mean duration of back pain was 7.3 years (range, 3 months-50 years), 123 (53.7%) attended 6 or more of the 8 sessions, 294 (86.0%) completed the study at 26 weeks, and 290 (84.8%) completed the study at 52 weeks. In intent-to-treat analyses at 26 weeks, the percentage of participants with clinically meaningful improvement on the RDQ was higher for those who received MBSR (60.5%) and CBT (57.7%) than for usual care (44.1%) (overall P = .04; relative risk [RR] for MBSR vs usual care, 1.37 [95% CI, 1.06-1.77]; RR for MBSR vs CBT, 0.95 [95% CI, 0.77-1.18]; and RR for CBT vs usual care, 1.31 [95% CI, 1.01-1.69]). The percentage of participants with clinically meaningful improvement in pain bothersomeness at 26 weeks was 43.6% in the MBSR group and 44.9% in the CBT group, vs 26.6% in the usual care group (overall P = .01; RR for MBSR vs usual care, 1.64 [95% CI, 1.15-2.34]; RR for MBSR vs CBT, 1.03 [95% CI, 0.78-1.36]; and RR for CBT vs usual care, 1.69 [95% CI, 1.18-2.41]). Findings for MBSR persisted with little change at 52 weeks for both primary outcomes. CONCLUSIONS AND RELEVANCE: Among adults with chronic low back pain, treatment with MBSR or CBT, compared with usual care, resulted in greater improvement in back pain and functional limitations at 26 weeks, with no significant differences in outcomes between MBSR and CBT. These findings suggest that MBSR may be an effective treatment option for patients with chronic low back pain. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01467843.

Simulation study comparing exposure matching with regression adjustment in an observational safety setting with group sequential monitoring.

Sequential methods are well established for randomized clinical trials (RCTs), and their use in observational settings has increased with the development of national vaccine and drug safety surveillance systems that monitor large healthcare databases. Observational safety monitoring requires that sequential testing methods be better equipped to incorporate confounder adjustment and accommodate rare adverse events. New methods designed specifically for observational surveillance include a group sequential likelihood ratio test that uses exposure matching and generalized estimating equations approach that involves regression adjustment. However, little is known about the statistical performance of these methods or how they compare to RCT methods in both observational and rare outcome settings. We conducted a simulation study to determine the type I error, power and time-to-surveillance-end of group sequential likelihood ratio test, generalized estimating equations and RCT methods that construct group sequential Lan-DeMets boundaries using data from a matched (group sequential Lan-DeMets-matching) or unmatched regression (group sequential Lan-DeMets-regression) setting. We also compared the methods using data from a multisite vaccine safety study. All methods had acceptable type I error, but regression methods were more powerful, faster at detecting true safety signals and less prone to implementation difficulties with rare events than exposure matching methods. Method performance also depended on the distribution of information and extent of confounding by site. Our results suggest that choice of sequential method, especially the confounder control strategy, is critical in rare event observational settings. These findings provide guidance for choosing methods in this context and, in particular, suggest caution when conducting exposure matching.

Access to supermarkets and fruit and vegetable consumption.

OBJECTIVES: We examined whether supermarket choice, conceptualized as a proxy for underlying personal factors, would better predict access to supermarkets and fruit and vegetable consumption than mere physical proximity. METHODS: The Seattle Obesity Study geocoded respondents' home addresses and locations of their primary supermarkets. Primary supermarkets were stratified into low, medium, and high cost according to the market basket cost of 100 foods. Data on fruit and vegetable consumption were obtained during telephone surveys. Linear regressions examined associations between physical proximity to primary supermarkets, supermarket choice, and fruit and vegetable consumption. Descriptive analyses examined whether supermarket choice outweighed physical proximity among lower-income and vulnerable groups. RESULTS: Only one third of the respondents shopped at their nearest supermarket for their primary food supply. Those who shopped at low-cost supermarkets were more likely to travel beyond their nearest supermarket. Fruit and vegetable consumption was not associated with physical distance but, with supermarket choice, after adjusting for covariates. CONCLUSIONS: Mere physical distance may not be the most salient variable to reflect access to supermarkets, particularly among those who shop by car. Studies on food environments need to focus beyond neighborhood geographic boundaries to capture actual food shopping behaviors.

Five-week outcomes from a dosing trial of therapeutic massage for chronic neck pain.

PURPOSE: This trial was designed to evaluate the optimal dose of massage for individuals with chronic neck pain. METHODS: We recruited 228 individuals with chronic nonspecific neck pain from an integrated health care system and the general population, and randomized them to 5 groups receiving various doses of massage (a 4-week course consisting of 30-minute visits 2 or 3 times weekly or 60-minute visits 1, 2, or 3 times weekly) or to a single control group (a 4-week period on a wait list). We assessed neck-related dysfunction with the Neck Disability Index (range, 0-50 points) and pain intensity with a numerical rating scale (range, 0-10 points) at baseline and 5 weeks. We used log-linear regression to assess the likelihood of clinically meaningful improvement in neck-related dysfunction (≥5 points on Neck Disability Index) or pain intensity (≥30% improvement) by treatment group. RESULTS: After adjustment for baseline age, outcome measures, and imbalanced covariates, 30-minute treatments were not significantly better than the wait list control condition in terms of achieving a clinically meaningful improvement in neck dysfunction or pain, regardless of the frequency of treatments. In contrast, 60-minute treatments 2 and 3 times weekly significantly increased the likelihood of such improvement compared with the control condition in terms of both neck dysfunction (relative risk = 3.41 and 4.98, P = .04 and .005, respectively) and pain intensity (relative risk = 2.30 and 2.73; P = .007 and .001, respectively). CONCLUSIONS: After 4 weeks of treatment, we found multiple 60-minute massages per week more effective than fewer or shorter sessions for individuals with chronic neck pain. Clinicians recommending massage and researchers studying this therapy should ensure that patients receive a likely effective dose of treatment.