Lehana Thabane

Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial

BACKGROUND Mobile (cell) phone communication has been suggested as a method to improve delivery of health services. However, data on the effects of mobile health technology on patient outcomes in resource-limited settings are limited. We aimed to assess whether mobile phone communication between health-care workers and patients starting antiretroviral therapy in Kenya improved drug adherence and suppression of plasma HIV-1 RNA load. METHODS WelTel Kenya1 was a multisite randomised clinical trial of HIV-infected adults initiating antiretroviral therapy (ART) in three clinics in Kenya. Patients were randomised (1:1) by simple randomisation with a random number generating program to a mobile phone short message service (SMS) intervention or standard care. Patients in the intervention group received weekly SMS messages from a clinic nurse and were required to respond within 48 h. Randomisation, laboratory assays, and analyses were done by investigators masked to treatment allocation; however, study participants and clinic staff were not masked to treatment. Primary outcomes were self-reported ART adherence (>95% of prescribed doses in the past 30 days at both 6 and 12 month follow-up visits) and plasma HIV-1 viral RNA load suppression (<400 copies per mL) at 12 months. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00830622. FINDINGS Between May, 2007, and October, 2008, we randomly assigned 538 participants to the SMS intervention (n=273) or to standard care (n=265). Adherence to ART was reported in 168 of 273 patients receiving the SMS intervention compared with 132 of 265 in the control group (relative risk [RR] for non-adherence 0·81, 95% CI 0·69-0·94; p=0·006). Suppressed viral loads were reported in 156 of 273 patients in the SMS group and 128 of 265 in the control group, (RR for virologic failure 0·84, 95% CI 0·71-0·99; p=0·04). The number needed to treat (NNT) to achieve greater than 95% adherence was nine (95% CI 5·0-29·5) and the NNT to achieve viral load suppression was 11 (5·8-227·3). INTERPRETATION Patients who received SMS support had significantly improved ART adherence and rates of viral suppression compared with the control individuals. Mobile phones might be effective tools to improve patient outcome in resource-limited settings. FUNDING US Presidents Emergency Plan for AIDS Relief.

Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses?

BACKGROUND Results from apparently conclusive meta-analyses may be false. A limited number of events from a few small trials and the associated random error may be under-recognized sources of spurious findings. The information size (IS, i.e. number of participants) required for a reliable and conclusive meta-analysis should be no less rigorous than the sample size of a single, optimally powered randomized clinical trial. If a meta-analysis is conducted before a sufficient IS is reached, it should be evaluated in a manner that accounts for the increased risk that the result might represent a chance finding (i.e. applying trial sequential monitoring boundaries). METHODS We analysed 33 meta-analyses with a sufficient IS to detect a treatment effect of 15% relative risk reduction (RRR). We successively monitored the results of the meta-analyses by generating interim cumulative meta-analyses after each included trial and evaluated their results using a conventional statistical criterion (alpha = 0.05) and two-sided Lan-DeMets monitoring boundaries. We examined the proportion of false positive results and important inaccuracies in estimates of treatment effects that resulted from the two approaches. RESULTS Using the random-effects model and final data, 12 of the meta-analyses yielded P > alpha = 0.05, and 21 yielded P </= alpha = 0.05. False positive interim results were observed in 3 out of 12 meta-analyses with P > alpha = 0.05. The monitoring boundaries eliminated all false positives. Important inaccuracies in estimates were observed in 6 out of 21 meta-analyses using the conventional P </= alpha = 0.05 and 0 out of 21 using the monitoring boundaries. CONCLUSIONS Evaluating statistical inference with trial sequential monitoring boundaries when meta-analyses fall short of a required IS may reduce the risk of false positive results and important inaccurate effect estimates.

The Number of Patients and Events Required to Limit the Risk of Overestimation of Intervention Effects in Meta-Analysis—A Simulation Study

Background Meta-analyses including a limited number of patients and events are prone to yield overestimated intervention effect estimates. While many assume bias is the cause of overestimation, theoretical considerations suggest that random error may be an equal or more frequent cause. The independent impact of random error on meta-analyzed intervention effects has not previously been explored. It has been suggested that surpassing the optimal information size (i.e., the required meta-analysis sample size) provides sufficient protection against overestimation due to random error, but this claim has not yet been validated. Methods We simulated a comprehensive array of meta-analysis scenarios where no intervention effect existed (i.e., relative risk reduction (RRR) = 0%) or where a small but possibly unimportant effect existed (RRR = 10%). We constructed different scenarios by varying the control group risk, the degree of heterogeneity, and the distribution of trial sample sizes. For each scenario, we calculated the probability of observing overestimates of RRR>20% and RRR>30% for each cumulative 500 patients and 50 events. We calculated the cumulative number of patients and events required to reduce the probability of overestimation of intervention effect to 10%, 5%, and 1%. We calculated the optimal information size for each of the simulated scenarios and explored whether meta-analyses that surpassed their optimal information size had sufficient protection against overestimation of intervention effects due to random error. Results The risk of overestimation of intervention effects was usually high when the number of patients and events was small and this risk decreased exponentially over time as the number of patients and events increased. The number of patients and events required to limit the risk of overestimation depended considerably on the underlying simulation settings. Surpassing the optimal information size generally provided sufficient protection against overestimation. Conclusions Random errors are a frequent cause of overestimation of intervention effects in meta-analyses. Surpassing the optimal information size will provide sufficient protection against overestimation.

The Cameroon Mobile Phone SMS (CAMPS) Trial: A Randomized Trial of Text Messaging versus Usual Care for Adherence to Antiretroviral Therapy

Background Mobile phone technology is a novel way of delivering health care and improving health outcomes. This trial investigates the use of motivational mobile phone text messages (SMS) to improve adherence to antiretroviral therapy (ART) over six months. Methodology/Principal Findings CAMPS was a single-site randomized two-arm parallel design trial in Yaoundé, Cameroon. We enrolled and randomized HIV-positive adults on ART, aged 21 years and above to receive a weekly standardized motivational text message versus usual care alone. The primary outcome was adherence measured using a visual analogue scale (VAS), number of doses missed (in the week preceding the interview) and pharmacy refill data. Outcomes were measured at 3 and 6 months. Service providers and outcome assessors were blinded to allocation. Analysis was by intention-to-treat. Between November and December 2010, 200 participants were randomized, with 101 in the intervention group and 99 in the control group. At 6 months, overall retention was 81.5%. We found no significant effect on adherence by VAS>95% (risk ratio [RR] 1.06, 95% confidence interval [CI] 0.89, 1.29; p = 0.542; reported missed doses (RR 1.01, 95% CI 0.87, 1.16; p>0.999) or number of pharmacy refills (mean difference [MD] 0.1, 95% CI: 0.23, 0.43; p = 0.617. One participant in the intervention arm reported a possible disclosure of status. Conclusions/Significance Standardized motivational mobile phone text messages did not significantly improve adherence to ART in this study. Other types of messaging or longer term studies are recommended. Registration 1. Pan-African Clinical Trials Registry; PACTR201011000261458 2. Clinicaltrials.gov; NCT01247181

Prednisolone and Mycobacterium indicus pranii in Tuberculous Pericarditis

BACKGROUND Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis. METHODS Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. RESULTS There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer. CONCLUSIONS In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).

Evolution of Heterogeneity (I2) Estimates and Their 95% Confidence Intervals in Large Meta-Analyses

Background Assessment of heterogeneity is essential in systematic reviews and meta-analyses of clinical trials. The most commonly used heterogeneity measure, I2, provides an estimate of the proportion of variability in a meta-analysis that is explained by differences between the included trials rather than by sampling error. Recent studies have raised concerns about the reliability of I2 estimates, due to their dependence on the precision of included trials and time-dependent biases. Authors have also advocated use of 95% confidence intervals (CIs) to express the uncertainty associated with I2 estimates. However, no previous studies have explored how many trials and events are required to ensure stable and reliable I2 estimates, or how 95% CIs perform as evidence accumulates. Methodology/Principal Findings To assess the stability and reliability of I2 estimates and their 95% CIs, in relation to the cumulative number of trials and events in meta-analysis, we looked at 16 large Cochrane meta-analyses - each including a sufficient number of trials and events to reliably estimate I2 - and monitored the I2 estimates and their 95% CIs for each year of publication. In 10 of the 16 meta-analyses, the I2 estimates fluctuated more than 40% over time. The median number of events and trials required before the cumulative I2 estimates stayed within +/−20% of the final I2 estimate was 467 and 11. No major fluctuations were observed after 500 events and 14 trials. The 95% confidence intervals provided good coverage over time. Conclusions/Significance I2 estimates need to be interpreted with caution when the meta-analysis only includes a limited number of events or trials. Confidence intervals for I2 estimates provide good coverage as evidence accumulates, and are thus valuable for reflecting the uncertainty associated with estimating I2.

Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer

The prevalence and risk factors for thromboembolism (TE) in children with cancer are largely unknown. This retrospective cohort study aims to determine the epidemiology of TE and to identify potential risk factors for TE in children with cancer.

Is mode of delivery associated with postpartum depression at 6 weeks: a prospective cohort study

Please cite this paper as: Sword W, Kurtz Landy C, Thabane L, Watt S, Krueger P, Farine D, Foster G. Is mode of delivery associated with postpartum depression at 6 weeks: a prospective cohort study. BJOG 2011;118:966–977.

Alternatives to Project-specific Consent for Access to Personal Information for Health Research: What Is the Opinion of the Canadian Public?

OBJECTIVES This study sought to determine public opinion on alternatives to project-specific consent for use of their personal information for health research. DESIGN The authors conducted a fixed-response random-digit dialed telephone survey of 1,230 adults across Canada. MEASUREMENTS We measured attitudes toward privacy and health research; trust in different institutions to keep information confidential; and consent choice for research use of ones own health information involving medical record review, automated abstraction of information from the electronic medical record, and linking education or income with health data. RESULTS Support was strong for both health research and privacy protection. Studying communicable diseases and quality of health care had greatest support (85% to 89%). Trust was highest for data institutes, university researchers, hospitals, and disease foundations (78% to 80%). Four percent of respondents thought information from their paper medical record should not be used at all for research, 32% thought permission should be obtained for each use, 29% supported broad consent, 24% supported notification and opt out, and 11% felt no need for notification or consent. Opinions were more polarized for automated abstraction of data from the electronic medical record. Respondents were more willing to link education with health data than income. CONCLUSIONS Most of the public supported alternatives to study-specific consent, but few supported use without any notification or consent. Consent choices for research use of ones health information should be documented in the medical record. The challenge remains how best to elicit those choices and ensure that they are up-to-date.

Efficacy of vitamin D supplementation in depression in adults: a systematic review.

CONTEXT Randomized controlled trials (RCTs) investigating the efficacy of vitamin D (Vit D) in depression provided inconsistent results. OBJECTIVE We aim to summarize the evidence of RCTs to assess the efficacy of oral Vit D supplementation in depression compared to placebo. DATA SOURCES We searched electronic databases, two conference proceedings, and gray literature by contacting authors of included studies. STUDY SELECTION We selected parallel RCTs investigating the effect of oral Vit D supplementation compared with placebo on depression in adults at risk of depression, with depression symptoms or a primary diagnosis of depression. DATA EXTRACTION Two reviewers independently extracted data from relevant literature. DATA SYNTHESIS Classical and Bayesian random-effects meta-analyses were used to pool relative risk, odds ratio, and standardized mean difference. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. RESULTS Six RCTs were identified with 1203 participants (72% females) including 71 depressed patients; five of the studies involved adults at risk of depression, and one trial used depressed patients. Results of the classical meta-analysis showed no significant effect of Vit D supplementation on postintervention depression scores (standardized mean difference = -0.14, 95% confidence interval = -0.41 to 0.13, P = .32; odds ratio = 0.93, 95% confidence interval = 0.54 to 1.59, P = .79). The quality of evidence was low. No significant differences were demonstrated in subgroup or sensitivity analyses. Similar results were found when Bayesian meta-analyses were applied. CONCLUSIONS There is insufficient evidence to support the efficacy of Vit D supplementation in depression symptoms, and more RCTs using depressed patients are warranted.