Lawrence Mbuagbaw

A tutorial on sensitivity analyses in clinical trials: the what, why, when and how

BackgroundSensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.DiscussionIn this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.SummaryWhen reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

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

Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis

Resuscitation with crystalloids compared with colloids for critically ill patients has been evaluated in large randomized, controlled trials (16) and meta-analyses (713). One meta-analysis(10) including 74 trials reported no difference in mortality between critically ill patients resuscitated with crystalloids and albumin (relative risk [RR], 1.01 [95% CI, 0.93 to 1.10]), hydroxyethyl starch (HES) (RR, 1.10 [CI, 0.91 to 1.32]), gelatin (RR, 0.91 [CI, 0.49 to 1.72]), or dextran (RR, 1.24 [CI, 0.94 to 1.65]). Another meta-analysis (8) reported that resuscitation with an albumin-containing solution in patients with sepsis may decrease mortality compared with solutions containing no albumin (RR, 0.82 [CI, 0.67 to 1.00]). Recent evidence suggests that starches, compared with other fluids and regardless of molecular weight, may be associated with acute kidney injury in the general population of critically ill patients and in those with sepsis (5, 11, 1315). A recent large pragmatic trial comparing colloids (mostly starches) with crystalloids (mostly 0.9% sodium chloride) suggested a 90-day mortality benefit with colloids (RR, 0.92 [CI, 0.86 to 0.99]) (16). Crystalloids can be characterized on the basis of tonicity and electrolyte content. The presence of an organic anion (for example, lactate, acetate, or gluconate) and correspondingly lower chloride content that more closely resembles the composition of plasma suggest that a crystalloid is balanced (for example, Ringer lactate and acetate solutions) (17). The most commonly used crystalloid, normal saline (0.9% sodium chloride), is far from normal, with a pH much less than 7.0 and a supraphysiologic chloride content of 154 mmol/L (18, 19). Compared with a balanced crystalloid solution, normal saline predisposes patients to hyperchloremic metabolic acidosis, decreased renal blood flow to the glomerulus, and impaired smooth-muscle contractility (20). Investigators have not done randomized, controlled trials (RCTs) comparing balanced and unbalanced crystalloids. However, 1 large beforeafter study of critically ill patients showed that balanced versus unbalanced fluid solution was associated with a lower incidence of acute kidney injury (8.4% vs. 14%; P< 0.01) and renal replacement therapy (6.3% vs. 10%; P= 0.05) but no differences in hospital mortality (18). Colloids include natural compounds, such as albumin, and synthetic compounds of HES, gelatin, or dextran. Expansion of plasma volume increases in proportion to the osmotic or oncotic potential, and colloids theoretically require less volume than crystalloids to achieve equivalent hemodynamic effect (19). Limitations of colloids include development of acute kidney injury and coagulation disorders with starches (14) and albumin creates risk for exposure to blood products (19). Another important consideration is the biochemical properties of the crystalloid solution in which the colloid is dissolved. For example, the chloride concentrations in HES may vary between 154 mmol/L (Voluven, Fresenius Kabi) and 118 mmol/L (Tetraspan, B. Braun Medical) (21). Whether any of these fluid properties translate into a survival advantage remains unclear, particularly regarding the optimal fluid for resuscitation in patients with sepsis. Fluid resuscitation, in addition to antibiotics and source control, is a cornerstone of initial management of sepsis (22). However, fluid management in patients with sepsis varies widely in practice (16, 23, 24). Meta-analyses of fluid resuscitation have been limited by not focusing on patients with sepsis (7, 9, 10), not considering electrolyte composition (5, 8, 10, 11), considering only 2 or 3 categories of fluid (25), not including direct and indirect comparisons in the same model, and omission of recent large RCTs(35, 16). Therefore, we did a network meta-analysis (NMA) considering direct and indirect comparisons of all types of fluid resuscitation tested in RCTs in patients with severe sepsis and septic shock, focusing on the effect of these interventions on mortality. Methods Data Sources and Searches This review was done using a predefined protocol. Initially, we searched MEDLINE (1948 to December 2012), EMBASE (1980 to December 2012), ACP Journal Club (1991 to December 2012), the Cochrane Central Register of Controlled Trials, HealthSTAR, the Allied and Complementary Medicine Database, and CINAHL. We updated the MEDLINE and EMBASE searches in August 2013 and March 2014. We screened previously published meta-analyses for relevant citations. Supplement 1 presents the search terms used. Supplement 1. WinBUGS Code for NMA Six reviewers working in 3 pairs screened the titles and abstracts to determine potential eligibility, and entries identified by any reviewer proceeded to the full-text eligibility review. Pretested eligibility forms were used for full-text review, which was also done in duplicate. A third adjudicator helped to resolve disagreements through consensus. Study Selection We selected parallel-group RCTs, including factorial designs, but excluded quasi-randomized and crossover trials. We excluded all studies published by Dr. Joachim Boldt because of suspected lack of integrity (26, 27). We did not apply restrictions on language or publication date. We included studies that involved adult (aged 16 years) critically ill patients with severe sepsis or septic shock as defined by the investigators and who required fluid resuscitation (defined as the administration of a bolus of intravenous fluid exceeding the amount required for maintenance or replacement fluids). We included studies with mixed critically ill populations whenever separate data for patients with sepsis were available. We excluded studies in which most patients had the systemic inflammatory response syndrome secondary to other causes (such as burn, pancreatitis, and trauma) without a clear sepsis subgroup and those focusing on patients after elective surgery. Interventions studied included any fluid or fluid strategy used for resuscitation compared with another fluid or fluid strategy. We excluded studies in which the primary goal was to assess short-term hemodynamic response. Our outcome was 90-day mortality or, if not available, 30-day, intensive care unit, or hospital mortality, whichever was longest. Data Extraction Pairs from the same 6 reviewers abstracted data in duplicate. Another clinician reviewed disagreements, and consensus was reached by discussion. We contacted authors of primary publications for missing or unclear information. Risk of Bias Independently and in duplicate, reviewers assessed risk of bias using a modified version of the Cochrane Collaboration assessment tool (28, 29). We judged each included study as having low, probably low, probably high, or high risk of bias for randomization-sequence generation, randomization concealment, blinding, incomplete data, selective reporting, and free of other bias (including intention-to-treat analysis). The overall rating of risk of bias for each study was the lowest rating for any of the criteria (Appendix Table). Appendix Table. Risk of Bias, by Study Data Synthesis and Analysis Our analysis classified fluids as crystalloids (divided into balanced and unbalanced solutions) and colloids (divided into albumin, gelatin, and low- and high-molecular-weight HES [threshold molecular weight, 150000 kDa]). We considered fluid balanced if it contained an anion of a weak acid (buffer) and its chloride content was correspondingly less than in 0.9% sodium chloride (21). The relevant analyses were a 4-node NMA (crystalloids vs. albumin vs. HES vs. gelatin), a 6-node NMA (crystalloids vs. albumin vs. HES vs. gelatin, with crystalloids divided into balanced or unbalanced and HES divided into low or high molecular weight), and a conventional direct frequentist fixed-effects meta-analytic comparison of crystalloids versus colloids. To calculate direct estimates of treatment effect for each pair of treatments in the 4- and 6-node networks, we did a frequentist fixed-effects meta-analysis. We reported the results as odds ratios (ORs) and corresponding 95% CIs. We evaluated heterogeneity by estimating the variance between studies (chi-square test and I 2 statistic) (30, 31). Using a Bayesian framework, we did 4- and 6-node fixed-effects NMAs for each treatment. We reported the results as ORs and corresponding 95% credibility intervals (CrIs), which are the Bayesian analogue of 95% CIs(32). The ORs reported are relative effects of compared fluids. The models are based on 80000 iterations with a burn-in of 40000 and a thin of 10. We used a random seed and vague priors. We assessed nonconvergence on the basis of BrooksGelmanRubin plots (33). We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess confidence in estimates of effect (quality of evidence) associated with specific comparisons, including estimates from direct, indirect, and final NMAs (Supplement 2) (34). Our confidence assessment addressed risk of bias, incoherence, imprecision, inconsistency, indirectness, and publication bias. Supplement 2. GRADE Confidence Explanations for All Point Estimates The starting point for confidence in direct and indirect estimates was high. However, indirect estimates were potentially rated down for intransitivity (that is, differences in patients, co-interventions, or settings that could lead to effect modification and thus a misleading comparison of fluid management strategies). We inferred confidence in indirect estimates by examining the connecting loops associated with the particular comparison. The confidence rating chosen was the lowest of the direct estimates contributing to the indirect comparison. For example, consider a comparison of A versus B that is informed by comparisons of A versus C and B versus C. If A versus C was rated as high confidence and B versus C as moderate confidence, the overall indirect confidence rating was ini

Mobile phone text messages for improving adherence to antiretroviral therapy (ART): a protocol for an individual patient data meta-analysis of randomised trials

Objectives Our objectives were to analyse the effects of text messaging versus usual care in improving adherence to antiretroviral therapy (ART) in people living with HIV using individual patient data meta-analysis. Adjusted, sensitivity and subgroup analyses were conducted. Setting 3 randomised controlled trials conducted between 2010 and 2012 in rural and urban centres in Cameroon and Kenya (two studies) were used. Participants A total of 1166 participants were included in this analysis (Cameroon=200; Kenya=428 and 538). Primary and secondary outcomes The primary outcome was adherence to ART >95%. The secondary outcomes were mortality, losses to follow-up, transfers and withdrawals. Results Text messaging improved adherence to ART (OR 1.38; 95% CIs 1.08 to 1.78; p=0.012), even after adjustment for baseline covariates (OR 1.46; 95% CI 1.13 to 1.88; p=0.004). Primary education (compared with no formal education) was associated with a greater intervention effect on adherence (OR 1.65; 95% CI 1.10 to 2.48; p=0.016) and also showed a significant subgroup effect (p=0.039). In sensitivity analysis, our findings were robust to a modified threshold of adherence, multiple imputation for missing data and aggregate level data pooling, but not to fixed-effects meta-analyses using generalised estimation equations. There was a significant subgroup effect for long weekly (p=0.037), short weekly text messages (p=0.014) and interactive messaging (p=0.010). Text messaging did not significantly affect any of the secondary outcomes. Conclusions Text messaging has a significant effect on adherence to ART, and this effect is influenced by level of education, gender, timing (weekly vs daily) and interactivity. We recommend the use of interactive weekly text messaging to improve adherence to ART, which is most effective in those with at least a primary level of education.

Male involvement in prevention programs of mother to child transmission of HIV: a systematic review to identify barriers and facilitators

BackgroundMany reports point to the beneficial effect of male partner involvement in programs for the prevention of mother-to-child-transmission (PMTCT) of HIV in curbing pediatric HIV infections. This paper summarizes the barriers and facilitators of male involvement in prevention programs of mother-to-child-transmission of HIV.MethodsWe searched PubMed, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published in English from 1998 to March 2012. We included studies conducted in a context of antenatal care or PMTCT of HIV reporting male actions that affected female uptake of PMTCT services. We did not target any specific interventions for this review.ResultsWe identified 24 studies from peer-reviewed journals; 21 from sub-Saharan Africa, 2 from Asia and 1 from Europe. Barriers to male PMTCT involvement were mainly at the level of the society, the health system and the individual. The most pertinent was the societal perception of antenatal care and PMTCT as a woman’s activity, and it was unacceptable for men to be involved. Health system factors such as long waiting times at the antenatal care clinic and the male unfriendliness of PMTCT services were also identified. The lack of communication within the couple, the reluctance of men to learn their HIV status, the misconception by men that their spouse’s HIV status was a proxy of theirs, and the unwillingness of women to get their partners involved due to fear of domestic violence, stigmatization or divorce were among the individual factors.Actions shown to facilitate male PMTCT involvement were either health system actions or factors directly tied to the individuals. Inviting men to the hospital for voluntary counseling and HIV testing and offering of PMTCT services to men at sites other than antenatal care were key health system facilitators. Prior knowledge of HIV and prior male HIV testing facilitated their involvement. Financial dependence of women was key to facilitating spousal involvement.ConclusionsThere is need for health system amendments and context-specific adaptations of public policy on PMTCT services to break down the barriers to and facilitate male PMTCT involvement.Trial RegistrationThe protocol for this review was registered with the International prospective register of systematic reviews (PROSPERO) record CRD42011001703.

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.

A systematic scoping review of adherence to reporting guidelines in health care literature

Background Reporting guidelines have been available for the past 17 years since the inception of the Consolidated Standards of Reporting Trials statement in 1996. These guidelines were developed to improve the quality of reporting of studies in medical literature. Despite the widespread availability of these guidelines, the quality of reporting of medical literature remained suboptimal. In this study, we assess the current adherence practice to reporting guidelines; determine key factors associated with better adherence to these guidelines; and provide recommendations to enhance adherence to reporting guidelines for future studies. Methods We undertook a systematic scoping review of systematic reviews of adherence to reporting guidelines across different clinical areas and study designs. We searched four electronic databases (Cumulative Index to Nursing and Allied Health Literature, Web of Science, Embase, and Medline) from January 1996 to September 2012. Studies were included if they addressed adherence to one of the following guidelines: Consolidated Standards of Reporting Trials (CONSORT), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Quality of Reporting of Meta-analysis (QUOROM), Transparent Reporting of Evaluations with Nonrandomized Designs (TREND), Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). A protocol for this study was devised. A literature search, data extraction, and quality assessment were performed independently by two authors in duplicate. This study reporting follows the PRISMA guidelines. Results Our search retrieved 5159 titles, of which 50 were eligible. Overall, 86.0% of studies reported suboptimal levels of adherence to reporting guidelines. Factors associated with better adherence included journal impact factor and endorsement of guidelines, publication date, funding source, multisite studies, pharmacological interventions and larger studies. Conclusion Reporting guidelines in the clinical literature are important to improve the standards of reporting of clinical studies; however, adherence to these guidelines remains suboptimal. Action is therefore needed to enhance the adherence to these standards. Strategies to enhance adherence include journal editorial policies endorsing these guidelines.

The cameroon mobile phone sms (CAMPS) trial: a protocol for a randomized controlled trial of mobile phone text messaging versus usual care for improving adherence to highly active anti-retroviral therapy

BackgroundThis trial aims at testing the efficacy of weekly reminder and motivational text messages, compared to usual care in improving adherence to Highly Active Antiretroviral Treatment in patients attending a clinic in Yaoundé, Cameroon.Methods and DesignThis is a single-centered randomized controlled single-blinded trial. A central computer generated randomization list will be generated using random block sizes. Allocation will be determined by sequentially numbered sealed opaque envelopes. 198 participants will either receive the mobile phone text message or usual care. Our hypothesis is that weekly motivational text messages can improve adherence to Highly Active Antiretroviral Treatment and other clinical outcomes in the control group by acting as a reminder, a cue to action and opening communication channels. Data will be collected at baseline, three months and six months. A blinded program secretary will send out text messages and record delivery.Our primary outcomes are adherence measured by the visual analogue scale, self report, and pharmacy refill data. Our secondary outcomes are clinical: weight, body mass index, opportunistic infections, all cause mortality and retention; biological: Cluster Designation 4 count and viral load; and quality of life. Analysis will be by intention-to-treat. Covariates and subgroups will be taken into account.DiscussionThis trial investigates the potential of SMS motivational reminders to improve adherence to Highly Active Antiretroviral Treatment in Cameroon. The intervention targets non-adherence due to forgetfulness and other forms of non-adherence.Trial RegistrationPan-African Clinical Trials Registry PACTR201011000261458http://clinicaltrials.gov/NCT01247181

Mobile phone text messaging interventions for HIV and other chronic diseases: an overview of systematic reviews and framework for evidence transfer

BackgroundStrong international commitment and the widespread use of antiretroviral therapy have led to higher longevity for people living with human immune deficiency virus (HIV). Text messaging interventions have been shown to improve health outcomes in people living with HIV. The objectives of this overview were to: map the state of the evidence of text messaging interventions, identify knowledge gaps, and develop a framework for the transfer of evidence to other chronic diseases.MethodsWe conducted a systematic review of systematic reviews on text messaging interventions to improve health or health related outcomes. We conducted a comprehensive search of PubMed, EMBASE (Exerpta Medica Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science (WoS) and the Cochrane Library on the 17th April 2014. Screening, data extraction and assessment of methodological quality were done in duplicate. Our findings were used to develop a conceptual framework for transfer.ResultsOur search identified 135 potential systematic reviews of which nine were included, reporting on 37 source studies, conducted in 19 different countries. Seven of nine (77.7%) of these reviews were high quality. There was some evidence for text messaging as a tool to improve adherence to antiretroviral therapy. Text messages also improved attendance at appointments and behaviour change outcomes. The findings were inconclusive for self-management of illness, treatment of tuberculosis and communicating results of medical investigations. The geographical distribution of text messaging research was limited to specific regions of the world. Prominent knowledge gaps included the absence of data on long term outcomes, patient satisfaction, and economic evaluations. The included reviews also identified methodological limitations in many of the primary studies.ConclusionsGlobal evidence supports the use of text messaging as a tool to improve adherence to medication and attendance at scheduled appointments. Given the similarities between HIV and other chronic diseases (long-term medications, life-long care, strong link to behaviour and the need for home-based support) evidence from HIV may be transferred to these diseases using our proposed framework by integration of HIV and chronic disease services or direct transfer.

Improvement in the quality of abstracts in major clinical journals since CONSORT extension for abstracts: A systematic review

BACKGROUND We sought to determine if the publication of the Consolidated Standards of Reporting Trials (CONSORT)(1) extension for abstracts in 2008 had led to an improvement in reporting abstracts of randomized controlled trials (RCTs).(2) METHODS: We searched PubMed for RCTs published in 2007 and 2012 in top-tier general medicine journals. A random selection of 100 trial abstracts was obtained for each year. Data were extracted in duplicate on the adherence to the CONSORT extension for abstracts. The primary outcome was the mean number of items reported and the secondary outcome was the odds of reporting each item. We also estimated incidence rate ratios (IRRs).(3) RESULTS: Significantly more checklist items were reported in 2012 than in 2007: adjusted mean difference was 2.91 (95% confidence interval [CI](4) 2.35, 3.41; p<0.001). In 2012 there were significant improvements in reporting the study as randomized in the title, describing the trial design, the participants, and objectives and blinding. In the Results section, trial status and numbers analyzed were also reported better. The IRRs were significantly higher for 2012 (IRR 1.32; 95% CI 1.25, 1.39; p<0.001) and in multisite studies compared to single site studies (IRR 1.08; 95% CI 1.03, 1.15; p=0.006). CONCLUSIONS There was a significant improvement in the reporting of abstracts of RCTs in 2012 compared to 2007. However, there is still room for improvement as some items remain under-reported.