Brittany B. Dennis

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.

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.

Testosterone suppression in opioid users: A systematic review and meta-analysis ☆

BACKGROUND Whether used for pain management or recreation, opioids have a number of adverse effects including hormonal imbalances. These imbalances have been reported to primarily involve testosterone and affect both males and females to the point of interfering with successful treatment and recovery. We conducted a systematic review and meta-analysis to determine the extent that opioids affect testosterone levels in both men and women, which may be relevant to improved treatment outcomes for opioid dependence and for pain management. METHODS We searched PubMed, EMBASE, PsycINFO, and CINAHL for relevant articles and included studies that examined testosterone levels in men and women while on opioids. Data collection was completed in duplicate. RESULTS Seventeen studies with 2769 participants (800 opioid users and 1969 controls) fulfilled the review inclusion criteria; 10 studies were cross-sectional and seven were cohort studies. Results showed a significant difference in mean testosterone level in men with opioid use compared to controls (MD=-164.78; 95% CI: -245.47, -84.08; p<0.0001). Methadone did not affect testosterone differently than other opioids. Testosterone levels in women were not affected by opioids. Generalizability of results was limited due to high heterogeneity among studies and overall low quality of evidence. CONCLUSIONS Our findings demonstrated that testosterone level is suppressed in men with regular opioid use regardless of opioid type. We found that opioids affect testosterone levels differently in men than women. This suggests that opioids, including methadone, may have different endocrine disruption mechanisms in men and women, which should be considered when treating opioid dependence.

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.

Impact of ABCB1 and CYP2B6 Genetic Polymorphisms on Methadone Metabolism, Dose and Treatment Response in Patients with Opioid Addiction: A Systematic Review and Meta-Analysis

Background Genetic variability may influence methadone metabolism, dose requirements, and risk of relapse. Objectives To determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment). Methods Two independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms. Results We screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05–1.00, p = 0.03) with minimal heterogeneity (I2 = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the *6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27–2.61, p = 0.02) however significant heterogeneity was observed (I2 = 69%). Carriers of the CYP2B6*6 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response. Conclusion Although the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers.

Sex differences in outcomes of methadone maintenance treatment for opioid addiction: a systematic review protocol

BackgroundUse of methadone for the treatment of opioid addiction is an effective harm-reduction approach, although variability in treatment outcomes among individuals has been reported. Men and women with opioid addiction have been known to differ in factors such as opioid use patterns and characteristics at treatment entry; however, little has been reported about differences in methadone treatment outcomes between men and women. Therefore, we present a protocol for a systematic review which aims to provide a summary of existing literature on sex differences in outcomes of methadone treatment for opioid addiction.Methods/DesignElectronic search of PubMed/MEDLINE, EMBASE, PsycINFO, and CINAHL databases will be conducted using a priori defined search strategy. Two authors (MB and BBD) will independently screen potential articles for eligibility using pre-determined inclusion and exclusion criteria and extract key information using a data extraction form designed for this study. Discrepancies will be resolved using a third party (ZS). The primary outcome will be sex differences in response to treatment defined as abstinence from illicit opioid use. We will also assess sex differences in treatment outcomes including treatment retention, remission status post-treatment, polysubstance abuse, methadone dose, drug-related adverse events, health status, psychological status, mortality, criminal activity, high risk sexual behavior, social support/relations, and employment. A meta-analysis will be conducted if possible; risk of bias and overall quality of evidence will be assessed to determine confidence in the estimates.DiscussionWe anticipate that this review will highlight how men and women differ in methadone treatment outcomes and allow us to generate conclusions that can be applied to treatment in a clinical setting.Systematic review registrationPROSPERO CRD42013006549

The effectiveness of opioid substitution treatments for patients with opioid dependence: a systematic review and multiple treatment comparison protocol

BackgroundOpioids are psychoactive analgesic drugs prescribed for pain relief and palliative care. Due to their addictive potential, effort and vigilance in controlling prescriptions is needed to avoid misuse and dependence. Despite the effort, the prevalence of opioid use disorder continues to rise. Opioid substitution therapies are commonly used to treat opioid dependence; however, there is minimal consensus as to which therapy is most effective. Available treatments include methadone, heroin, buprenorphine, as well as naltrexone. This systematic review aims to assess and compare the effect of all available opioid substitution therapies on the treatment of opioid dependence.Methods/DesignThe authors will search Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform Search Portal, and the National Institutes for Health Clinical Trials Registry. The title, abstract, and full-text screening will be completed in duplicate. When appropriate, multiple treatment comparison Bayesian meta-analytic methods will be performed to deduce summary statistics estimating the effectiveness of all opioid substitution therapies in terms of retention and response to treatment (as measured through continued opioid abuse).DiscussionUsing evidence gained from this systematic review, we anticipate disseminating an objective review of the current available literature on the effectiveness of all opioid substitution therapies for the treatment of opioid use disorder. The results of this systematic review are imperative to the further enhancement of clinical practice in addiction medicine.Systematic review registrationPROSPERO CRD42013006507.

Methadone induces testosterone suppression in patients with opioid addiction

Sex hormones may have a role in the pathophysiology of substance use disorders, as demonstrated by the association between testosterone and addictive behaviour in opioid dependence. Although opioid use has been found to suppress testosterone levels in men and women, the extent of this effect and how it relates to methadone treatment for opioid dependence is unclear. The present multi-centre cross-sectional study consecutively recruited 231 patients with opioid dependence from methadone clinics across Ontario, Canada between June and December of 2011. We obtained demographic details, substance use, psychiatric history, and blood and urine samples from enrolled subjects. The control group included 783 non-opioid using adults recruited from a primary care setting in Ontario, Canada. Average testosterone level in men receiving methadone treatment was significantly lower than controls. No effect of opioids including methadone on testosterone level in women was found and testosterone did not fluctuate significantly between menstrual cycle phases. In methadone patients, testosterone level was significantly associated with methadone dose in men only. We recommend that testosterone levels be checked in men prior and during methadone and other opioid therapy, in order to detect and treat testosterone deficiency associated with opioids and lead to successful methadone treatment outcomes.

The role of the serotonergic system in suicidal behavior.

Serotonin is a widely investigated neurotransmitter in several psychopathologies, including suicidal behavior (SB); however, its role extends to several physiological functions involving the nervous system, as well as the gastrointestinal and cardiovascular systems. This review summarizes recent research into ten serotonergic genes related to SB. These genes – TPH1, TPH2, SLC6A4, SLC18A2, HTR1A, HTR1B, HTR2A, DDC, MAOA, and MAOB – encode proteins that are vital to serotonergic function: tryptophan hydroxylase; the serotonin transporter 5-HTT; the vesicular transporter VMAT2; the HTR1A, HTR1B, and HTR2A receptors; the L-amino acid decarboxylase; and the monoamine oxidases. This review employed a systematic search strategy and a narrative research methodology to disseminate the current literature investigating the link between SB and serotonin.

Assessing the quality of published genetic association studies in meta-analyses: the quality of genetic studies (Q-Genie) tool.

BackgroundAdvances in genomics technology have led to a dramatic increase in the number of published genetic association studies. Systematic reviews and meta-analyses are a common method of synthesizing findings and providing reliable estimates of the effect of a genetic variant on a trait of interest. However, summary estimates are subject to bias due to the varying methodological quality of individual studies. We embarked on an effort to develop and evaluate a tool that assesses the quality of published genetic association studies. Performance characteristics (i.e. validity, reliability, and item discrimination) were evaluated using a sample of thirty studies randomly selected from a previously conducted systematic review.ResultsThe tool demonstrates excellent psychometric properties and generates a quality score for each study with corresponding ratings of ‘low’, ‘moderate’, or ‘high’ quality. We applied our tool to a published systematic review to exclude studies of low quality, and found a decrease in heterogeneity and an increase in precision of summary estimates.ConclusionThis tool can be used in systematic reviews to inform the selection of studies for inclusion, to conduct sensitivity analyses, and to perform meta-regressions.