A systematic review and network meta-analysis of topical pharmacological, oral pharmacological, physical and combined treatments for acne vulgaris.

BACKGROUND: Various treatments for acne vulgaris exist, but little is known about their comparative effectiveness in relation to acne severity. OBJECTIVES: To identify best treatments for mild-to-moderate and moderate-to-severe acne, as determined by clinician-assessed morphological features. METHODS: We undertook a systematic review and network meta-analysis of randomized controlled trials (RCTs) assessing topical pharmacological, oral pharmacological, physical and combined treatments for mild-to-moderate and moderate-to-severe acne, published up to May 2020. Outcomes included percentage change in total lesion count from baseline, treatment discontinuation for any reason, and discontinuation owing to side-effects. Risk of bias was assessed using the Cochrane risk-of-bias tool and bias adjustment models. Effects for treatments with ≥ 50 observations each compared with placebo are reported below. RESULTS: We included 179 RCTs with approximately 35 000 observations across 49 treatment classes. For mild-to-moderate acne, the most effective options for each treatment type were as follows: topical pharmacological - combined retinoid with benzoyl peroxide (BPO) [mean difference 26·16%, 95% credible interval (CrI) 16·75-35·36%]; physical - chemical peels, e.g. salicylic or mandelic acid (39·70%, 95% CrI 12·54-66·78%) and photochemical therapy (combined blue/red light) (35·36%, 95% CrI 17·75-53·08%). Oral pharmacological treatments (e.g. antibiotics, hormonal contraceptives) did not appear to be effective after bias adjustment. BPO and topical retinoids were less well tolerated than placebo. For moderate-to-severe acne, the most effective options for each treatment type were as follows: topical pharmacological - combined retinoid with lincosamide (clindamycin) (44·43%, 95% CrI 29·20-60·02%); oral pharmacological - isotretinoin of total cumulative dose ≥ 120 mg kg-1 per single course (58·09%, 95% CrI 36·99-79·29%); physical - photodynamic therapy (light therapy enhanced by a photosensitizing chemical) (40·45%, 95% CrI 26·17-54·11%); combined - BPO with topical retinoid and oral tetracycline (43·53%, 95% CrI 29·49-57·70%). Topical retinoids and oral tetracyclines were less well tolerated than placebo. The quality of included RCTs was moderate to very low, with evidence of inconsistency between direct and indirect evidence. Uncertainty in findings was high, in particular for chemical peels, photochemical therapy and photodynamic therapy. However, conclusions were robust to potential bias in the evidence. CONCLUSIONS: Topical pharmacological treatment combinations, chemical peels and photochemical therapy were most effective for mild-to-moderate acne. Topical pharmacological treatment combinations, oral antibiotics combined with topical pharmacological treatments, oral isotretinoin and photodynamic therapy were most effective for moderate-to-severe acne. Further research is warranted for chemical peels, photochemical therapy and photodynamic therapy for which evidence was more limited. What is already known about this topic? Acne vulgaris is the eighth most common disease globally. Several topical, oral, physical and combined treatments for acne vulgaris exist. Network meta-analysis (NMA) synthesizes direct and indirect evidence and allows simultaneous inference for all treatments forming an evidence network. Previous NMAs have assessed a limited range of treatments for acne vulgaris and have not evaluated effectiveness of treatments for moderate-to-severe acne. What does this study add? For mild-to-moderate acne, topical treatment combinations, chemical peels, and photochemical therapy (combined blue/red light; blue light) are most effective. For moderate-to-severe acne, topical treatment combinations, oral antibiotics combined with topical treatments, oral isotretinoin and photodynamic therapy (light therapy enhanced by a photosensitizing chemical) are most effective. Based on these findings, along with further clinical and cost-effectiveness considerations, National Institute for Health and Care Excellence (NICE) guidance recommends, as first-line treatments, fixed topical treatment combinations for mild-to-moderate acne and fixed topical treatment combinations, or oral tetracyclines combined with topical treatments, for moderate-to-severe acne.

Cost-effectiveness of topical pharmacological, oral pharmacological, physical and combined treatments for acne vulgaris.

BACKGROUND: Acne vulgaris is a common skin condition that may cause psychosocial distress. There is evidence that topical treatment combinations, chemical peels and photochemical therapy (combined blue/red light) are effective for mild-to-moderate acne, while topical treatment combinations, oral antibiotics combined with topical treatments, oral isotretinoin and photodynamic therapy are most effective for moderate-to-severe acne. Effective treatments have varying costs. The National Institute for Health and Care Excellence (NICE) in England considers cost-effectiveness when producing national clinical, public health and social care guidance. AIM: To assess the cost-effectiveness of treatments for mild-to-moderate and moderate-to-severe acne to inform relevant NICE guidance. METHODS: A decision-analytical model compared costs and quality-adjusted life-years (QALYs) of effective topical pharmacological, oral pharmacological, physical and combined treatments for mild-to-moderate and moderate-to-severe acne, from the perspective of the National Health Service in England. Effectiveness data were derived from a network meta-analysis. Other model input parameters were based on published sources, supplemented by expert opinion. RESULTS: All of the assessed treatments were more cost-effective than treatment with placebo (general practitioner visits without active treatment). For mild-to-moderate acne, topical treatment combinations and photochemical therapy (combined blue/red light) were most cost-effective. For moderate-to-severe acne, topical treatment combinations, oral antibiotics combined with topical treatments, and oral isotretinoin were the most cost-effective. Results showed uncertainty, as reflected in the wide confidence intervals around mean treatment rankings. CONCLUSION: A range of treatments are cost-effective for the management of acne. Well-conducted studies are needed to examine the long-term clinical efficacy and cost-effectiveness of the full range of acne treatments.

Psychological treatments for post-traumatic stress disorder in adults: a network meta-analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a potentially chronic and disabling disorder affecting a significant minority of people exposed to trauma. Various psychological treatments have been shown to be effective, but their relative effects are not well established. METHODS: We undertook a systematic review and network meta-analyses of psychological interventions for adults with PTSD. Outcomes included PTSD symptom change scores post-treatment and at 1-4-month follow-up, and remission post-treatment. RESULTS: We included 90 trials, 6560 individuals and 22 interventions. Evidence was of moderate-to-low quality. Eye movement desensitisation and reprocessing (EMDR) [standardised mean difference (SMD) -2.07; 95% credible interval (CrI) -2.70 to -1.44], combined somatic/cognitive therapies (SMD -1.69; 95% CrI -2.66 to -0.73), trauma-focused cognitive behavioural therapy (TF-CBT) (SMD -1.46; 95% CrI -1.87 to -1.05) and self-help with support (SMD -1.46; 95% CrI -2.33 to -0.59) appeared to be most effective at reducing PTSD symptoms post-treatment v. waitlist, followed by non-TF-CBT, TF-CBT combined with a selective serotonin reuptake inhibitor (SSRI), SSRIs, self-help without support and counselling. EMDR and TF-CBT showed sustained effects at 1-4-month follow-up. EMDR, TF-CBT, self-help with support and counselling improved remission rates post-treatment. Results for other interventions were either inconclusive or based on limited evidence. CONCLUSIONS: EMDR and TF-CBT appear to be most effective at reducing symptoms and improving remission rates in adults with PTSD. They are also effective at sustaining symptom improvements beyond treatment endpoint. Further research needs to explore the long-term comparative effectiveness of psychological therapies for adults with PTSD and also the impact of severity and complexity of PTSD on treatment outcomes.

Research Review: Psychological and psychosocial treatments for children and young people with post-traumatic stress disorder: a network meta-analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a potentially chronic and disabling disorder that affects a significant minority of youth exposed to trauma. Previous studies have concluded that trauma-focused cognitive behavioural therapy (TF-CBT) is an effective treatment for PTSD in youth, but the relative strengths of different psychological therapies are poorly understood. METHODS: We undertook a systematic review and network meta-analyses of psychological and psychosocial interventions for children and young people with PTSD. Outcomes included PTSD symptom change scores post-treatment and at 1-4-month follow-up, and remission post-treatment. RESULTS: We included 32 trials of 17 interventions and 2,260 participants. Overall, the evidence was of moderate-to-low quality. No inconsistency was detected between direct and indirect evidence. Individual forms of TF-CBT showed consistently large effects in reducing PTSD symptoms post-treatment compared with waitlist. The order of interventions by descending magnitude of effect versus waitlist was as follows: cognitive therapy for PTSD (SMD -2.94, 95%CrI -3.94 to -1.95), combined somatic/cognitive therapies, child-parent psychotherapy, combined TF-CBT/parent training, meditation, narrative exposure, exposure/prolonged exposure, play therapy, Cohen TF-CBT/cognitive processing therapy (CPT), eye movement desensitisation and reprocessing (EMDR), parent training, group TF-CBT, supportive counselling and family therapy (SMD -0.37, 95%CrI -1.60 to 0.84). Results for parent training, supportive counselling and family therapy were inconclusive. Cohen TF-CBT/CPT, group TF-CBT and supportive counselling had the largest evidence base. Results regarding changes in PTSD symptoms at follow-up and remission post-treatment were uncertain due to limited evidence. CONCLUSIONS: Trauma-focused cognitive behavioural therapy, in particular individual forms, appears to be most effective in the management of PTSD in youth. EMDR is effective but to a lesser extent. Supportive counselling does not appear to be effective. Results suggest a large positive effect for emotional freedom technique, child-parent psychotherapy, combined TF-CBT/parent training, and meditation, but further research is needed to confirm these findings as they were based on very limited evidence.

Cost-effectiveness of psychological interventions for children and young people with post-traumatic stress disorder.

BACKGROUND: PTSD in youth may lead to long-lasting psychological implications, educational difficulties and increased healthcare costs. Psychological interventions have been shown to be effective in its management. The objective of this study was to assess the cost-effectiveness of a range of psychological interventions for children and young people with PTSD. METHODS: A decision-analytic model was constructed to compare costs and quality-adjusted life years (QALYs) of 10 psychological interventions and no treatment for children and young people with PTSD, from the perspective of the National Health Service and personal social services in England. Effectiveness data were derived from a systematic review and network meta-analysis. Other model input parameters were based on published sources, supplemented by expert opinion. RESULTS: Cognitive therapy for PTSD, a form of individual trauma-focused cognitive behavioural therapy (TF-CBT), appeared to be the most cost-effective intervention for children and young people with PTSD (with a probability of .78 amongst the 11 evaluated options at a cost-effectiveness threshold of £20,000/QALY), followed by narrative exposure (another form of individual TF-CBT), play therapy, and other forms of individual TF-CBT. After excluding cognitive therapy from the analysis, narrative exposure appeared to be the most cost-effective option with a .40 probability of being cost-effective amongst the remaining 10 options. EMDR, parent training and group TF-CBT occupied middle cost-effectiveness rankings. Family therapy and supportive counselling were less cost-effective than other active interventions. There was limited evidence for some interventions, in particular cognitive therapy for PTSD and parent training. CONCLUSIONS: Individual forms of TF-CBT and, to a lesser degree, play therapy appear to be cost-effective in the treatment of children and young people with PTSD. Family therapy and supportive counselling are unlikely to be cost-effective relative to other interventions. There is a need for well-conducted studies that examine the long-term clinical and cost-effectiveness of a range of psychological treatments for children and young people with PTSD.

Spie charts for quantifying treatment effectiveness and safety in multiple outcome network meta-analysis: a proof-of-concept study.

BACKGROUND: Network meta-analysis (NMA) simultaneously synthesises direct and indirect evidence on the relative efficacy and safety of at least three treatments. A decision maker may use the coherent results of an NMA to determine which treatment is best for a given outcome. However, this evidence must be balanced across multiple outcomes. This study aims to provide a framework that permits the objective integration of the comparative effectiveness and safety of treatments across multiple outcomes. METHODS: In the proposed framework, measures of each treatment's performance are plotted on its own pie chart, superimposed on another pie chart representing the performance of a hypothetical treatment that is the best across all outcomes. This creates a spie chart for each treatment, where the coverage area represents the probability a treatment ranks best overall. The angles of each sector may be adjusted to reflect the importance of each outcome to a decision maker. The framework is illustrated using two published NMA datasets comparing dietary oils and fats and psoriasis treatments. Outcome measures are plotted in terms of the surface under the cumulative ranking curve. The use of the spie chart was contrasted with that of the radar plot. RESULTS: In the NMA comparing the effects of dietary oils and fats on four lipid biomarkers, the ease of incorporating the lipids' relative importance on spie charts was demonstrated using coefficients from a published risk prediction model on coronary heart disease. Radar plots produced two sets of areas based on the ordering of the lipids on the axes, while the spie chart only produced one set. In the NMA comparing psoriasis treatments, the areas inside spie charts containing both efficacy and safety outcomes masked critical information on the treatments' comparative safety. Plotting the areas inside spie charts of the efficacy outcomes against measures of the safety outcome facilitated simultaneous comparisons of the treatments' benefits and harms. CONCLUSIONS: The spie chart is more optimal than a radar plot for integrating the comparative effectiveness or safety of a treatment across multiple outcomes. Formal validation in the decision-making context, along with statistical comparisons with other recent approaches are required.

Characteristics and knowledge synthesis approach for 456 network meta-analyses: a scoping review.

BACKGROUND: Network meta-analysis (NMA) has become a popular method to compare more than two treatments. This scoping review aimed to explore the characteristics and methodological quality of knowledge synthesis approaches underlying the NMA process. We also aimed to assess the statistical methods applied using the Analysis subdomain of the ISPOR checklist. METHODS: Comprehensive literature searches were conducted in MEDLINE, PubMed, EMBASE, and Cochrane Database of Systematic Reviews from inception until April 14, 2015. References of relevant reviews were scanned. Eligible studies compared at least four different interventions from randomised controlled trials with an appropriate NMA approach. Two reviewers independently performed study selection and data abstraction of included articles. All discrepancies between reviewers were resolved by a third reviewer. Data analysis involved quantitative (frequencies) and qualitative (content analysis) methods. Quality was evaluated using the AMSTAR tool for the conduct of knowledge synthesis and the ISPOR tool for statistical analysis. RESULTS: After screening 3538 citations and 877 full-text papers, 456 NMAs were included. These were published between 1997 and 2015, with 95% published after 2006. Most were conducted in Europe (51%) or North America (31%), and approximately one-third reported public sources of funding. Overall, 84% searched two or more electronic databases, 62% searched for grey literature, 58% performed duplicate study selection and data abstraction (independently), and 62% assessed risk of bias. Seventy-eight (17%) NMAs relied on previously conducted systematic reviews to obtain studies for inclusion in their NMA. Based on the AMSTAR tool, almost half of the NMAs incorporated quality appraisal results to formulate conclusions, 36% assessed publication bias, and 16% reported the source of funding. Based on the ISPOR tool, half of the NMAs did not report if an assessment for consistency was conducted or whether they accounted for inconsistency when present. Only 13% reported heterogeneity assumptions for the random-effects model. CONCLUSIONS: The knowledge synthesis methods and analytical process for NMAs are poorly reported and need improvement.

Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Poly(ADP-ribose) polymerase inhibitors (PARPi) are a novel option to treat patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib plus abiraterone acetate and prednisone (AAP) is indicated for BRCA1/2 mutation-positive mCRPC. Niraparib plus AAP demonstrated safety and efficacy in the phase 3 MAGNITUDE trial (NCT03748641). In the absence of head-to-head studies comparing PARPi regimens, the feasibility of conducting indirect treatment comparisons (ITC) to inform decisions for patients with first-line BRCA1/2 mutation-positive mCRPC has been explored. METHODS: A systematic literature review was conducted to identify evidence from randomized controlled trials on relevant comparators to inform the feasibility of conducting ITCs via network meta-analysis (NMA) or population-adjusted indirect comparisons (PAIC). Feasibility was assessed based on network connectivity, data availability in the BRCA1/2 mutation-positive population, and degree of within- and between-study heterogeneity or bias. RESULTS: NMAs between niraparib plus AAP and other PARPi regimens (olaparib monotherapy, olaparib plus AAP, and talazoparib plus enzalutamide) were inappropriate due to the disconnected network, differences in trial populations related to effect modifiers, or imbalances within BRCA1/2 mutation-positive subgroups. The latter issue, coupled with the lack of a common comparator (except for olaparib plus AAP), also rendered anchored PAICs infeasible. Unanchored PAICs were either inappropriate due to lack of population overlap (vs. olaparib monotherapy) or were restricted by unmeasured confounders and small sample size (vs. olaparib plus AAP). PAIC versus talazoparib plus enzalutamide was not possible due to lack of published arm-level baseline characteristics and sufficient efficacy outcome data in the relevant population. CONCLUSION: The current randomized controlled trial evidence network does not permit robust comparisons between niraparib plus AAP and other PARPi regimens for patients with 1L BRCA-positive mCRPC. Decision-makers should scrutinize any ITC results in light of their limitations. Real-world evidence combined with clinical experience should inform treatment recommendations in this indication.

Network meta-interpolation: Effect modification adjustment in network meta-analysis using subgroup analyses.

Effect modification (EM) may cause bias in network meta-analysis (NMA). Existing population adjustment NMA methods use individual patient data to adjust for EM but disregard available subgroup information from aggregated data in the evidence network. Additionally, these methods often rely on the shared effect modification (SEM) assumption. In this paper, we propose Network Meta-Interpolation (NMI): a method using subgroup analyses to adjust for EM that does not assume SEM. NMI balances effect modifiers across studies by turning treatment effect (TE) estimates at the subgroup- and study level into TE and standard errors at EM values common to all studies. In an extensive simulation study, we simulate two evidence networks consisting of four treatments, and assess the impact of departure from the SEM assumption, variable EM correlation across trials, trial sample size and network size. NMI was compared to standard NMA, network meta-regression (NMR) and Multilevel NMR (ML-NMR) in terms of estimation accuracy and credible interval (CrI) coverage. In the base case non-SEM dataset, NMI achieved the highest estimation accuracy with root mean squared error (RMSE) of 0.228, followed by standard NMA (0.241), ML-NMR (0.447) and NMR (0.541). In the SEM dataset, NMI was again the most accurate method with RMSE of 0.222, followed by ML-NMR (0.255). CrI coverage followed a similar pattern. NMI's dominance in terms of estimation accuracy and CrI coverage appeared to be consistent across all scenarios. NMI represents an effective option for NMA in the presence of study imbalance and available subgroup data.

What is the optimal management of potentially resectable stage III-N2 NSCLC? Results of a fixed-effects network meta-analysis and economic modelling.

Introduction: There is a critical need to understand the optimal treatment regimen in patients with potentially resectable stage III-N2 nonsmall cell lung cancer (NSCLC). Methods: A systematic review of randomised controlled trials was carried out using a literature search including the CDSR, CENTRAL, DARE, HTA, EMBASE and MEDLINE bibliographic databases. Selected trials were used to perform a Bayesian fixed-effects network meta-analysis and economic modelling of treatment regimens relevant to current-day treatment options: chemotherapy plus surgery (CS), chemotherapy plus radiotherapy (CR) and chemoradiotherapy followed by surgery (CRS). Findings: Six trials were prioritised for evidence synthesis. The fixed-effects network meta-analyses demonstrated an improvement in disease-free survival (DFS) for CRS versus CS and CRS versus CR of 0.34 years (95% CI 0.02-0.65) and 0.32 years (95% CI 0.05-0.58) respectively, over a 5-year period. No evidence of effect was observed in overall survival although point estimates favoured CRS. The probabilities that CRS had a greater mean survival time and greater probability of being alive than the reference treatment of CR at 5 years were 89% and 86% respectively. Survival outcomes for CR and CS were essentially equivalent. The economic model calculated that CRS and CS had incremental cost-effectiveness ratios of £19 000/quality-adjusted life-year (QALY) and £78 000/QALY compared to CR. The probability that CRS generated more QALYs than CR and CS was 94%. Interpretation: CRS provides an extended time in a disease-free state leading to improved cost-effectiveness over CR and CS in potentially resectable stage III-N2 NSCLC.

Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children.

BACKGROUND: Pediatric healthcare is critically dependent on the availability of accurate and precise laboratory biomarkers of pediatric disease, and on the availability of reference intervals to allow appropriate clinical interpretation. The development and growth of children profoundly influence normal circulating concentrations of biochemical markers and thus the respective reference intervals. There are currently substantial gaps in our knowledge of the influences of age, sex, and ethnicity on reference intervals. We report a comprehensive covariate-stratified reference interval database established from a healthy, nonhospitalized, and multiethnic pediatric population. METHODS: Healthy children and adolescents (n = 2188, newborn to 18 years of age) were recruited from a multiethnic population with informed parental consent and were assessed from completed questionnaires and according to defined exclusion criteria. Whole-blood samples were collected for establishing age- and sex-stratified reference intervals for 40 serum biochemical markers (serum chemistry, enzymes, lipids, proteins) on the Abbott ARCHITECT c8000 analyzer. RESULTS: Reference intervals were generated according to CLSI C28-A3 statistical guidelines. Caucasians, East Asians, and South Asian participants were evaluated with respect to the influence of ethnicity, and statistically significant differences were observed for 7 specific biomarkers. CONCLUSIONS: The establishment of a new comprehensive database of pediatric reference intervals is part of the Canadian Laboratory Initiative in Pediatric Reference Intervals (CALIPER). It should assist laboratorians and pediatricians in interpreting test results more accurately and thereby lead to improved diagnosis of childhood diseases and reduced patient risk. The database will also be of global benefit once reference intervals are validated in transference studies with other analytical platforms and local populations, as recommended by the CLSI.

Software to Conduct a Meta-Analysis and Network Meta-Analysis.

Statistical software for meta-analysis (MA) and network meta-analysis (NMA) have become indispensable for researchers. The aim of this chapter is to introduce key features of MA and NMA software to compare the effectiveness of interventions. Commonly used or routinely maintained statistical software are reviewed, including commercial and open-sourced programs such as Stata, R and Excel plug-ins. It does not provide a comprehensive overview of all features available in the software covered. Rather, it focuses on the essential features required to carry out an MA or NMA . This chapter begins with a review of key considerations when implementing an MA or NMA , then presents a summary of the software. Key features of each software option are discussed.

A non-parametric approach for jointly combining evidence on progression free and overall survival time in network meta-analysis.

Randomised controlled trials of cancer treatments typically report progression free survival (PFS) and overall survival (OS) outcomes. Existing methods to synthesise evidence on PFS and OS either rely on the proportional hazards assumption or make parametric assumptions which may not capture the diverse survival curve shapes across studies and treatments. Furthermore, PFS and OS are not independent; OS is the sum of PFS and post-progression survival (PPS). Our aim was to develop a non-parametric approach for jointly synthesising evidence from published Kaplan-Meier survival curves of PFS and OS without assuming proportional hazards. Restricted mean survival times (RMST) are estimated by the area under the survival curves (AUCs) up to a restricted follow-up time. The correlation between AUCs due to the constraint that OS > PFS is estimated using bootstrap re-sampling. Network meta-analysis models are given for RMST for PFS and PPS and ensure that OS = PFS + PPS. Both additive and multiplicative network meta-analysis models are presented to obtain relative treatment effects as either differences or ratios of RMST. The methods are illustrated with a network meta-analysis of treatments for stage IIIA-N2 non-small cell lung cancer. The approach has implications for health economic models of cancer treatments, which require estimates of the mean time spent in the PFS and PPS health-states. The methods can be applied to a single time-to-event outcome, and so have wide applicability in any field where time-to-event outcomes are reported, the proportional hazards assumption is in doubt, and survival curve shapes differ across studies and interventions.

Cost-effectiveness of psychological treatments for post-traumatic stress disorder in adults.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a severe and disabling condition that may lead to functional impairment and reduced productivity. Psychological interventions have been shown to be effective in its management. The objective of this study was to assess the cost-effectiveness of a range of interventions for adults with PTSD. METHODS: A decision-analytic model was constructed to compare costs and quality-adjusted life-years (QALYs) of 10 interventions and no treatment for adults with PTSD, from the perspective of the National Health Service and personal social services in England. Effectiveness data were derived from a systematic review and network meta-analysis. Other model input parameters were based on published sources, supplemented by expert opinion. RESULTS: Eye movement desensitisation and reprocessing (EMDR) appeared to be the most cost-effective intervention for adults with PTSD (with a probability of 0.34 amongst the 11 evaluated options at a cost-effectiveness threshold of £20,000/QALY), followed by combined somatic/cognitive therapies, self-help with support, psychoeducation, selective serotonin reuptake inhibitors (SSRIs), trauma-focused cognitive behavioural therapy (TF-CBT), self-help without support, non-TF-CBT and combined TF-CBT/SSRIs. Counselling appeared to be less cost-effective than no treatment. TF-CBT had the largest evidence base. CONCLUSIONS: A number of interventions appear to be cost-effective for the management of PTSD in adults. EMDR appears to be the most cost-effective amongst them. TF-CBT has the largest evidence base. There remains a need for well-conducted studies that examine the long-term clinical and cost-effectiveness of a range of treatments for adults with PTSD.

Empirical evaluation of SUCRA-based treatment ranks in network meta-analysis: quantifying robustness using Cohen's kappa.

OBJECTIVE: To provide a framework for quantifying the robustness of treatment ranks based on Surface Under the Cumulative RAnking curve (SUCRA) in network meta-analysis (NMA) and investigating potential factors associated with lack of robustness. METHODS: We propose the use of Cohen's kappa to quantify the agreement between SUCRA-based treatment ranks estimated through NMA of a complete data set and a subset of it. We illustrate our approach using five published NMA data sets, where robustness was assessed by removing studies one at a time. RESULTS: Overall, SUCRA-based treatment ranks were robust to individual studies in the five data sets we considered. We observed more incidences of disagreement between ranks in the networks with larger numbers of treatments. Most treatments moved only one or two ranks up or down. The lowest quadratic weighted kappa estimate observed across all networks was in the network with the smallest number of treatments (4), where weighted kappa=40%. In the network with the largest number of treatments (12), the lowest observed quadratic weighted kappa=89%, reflecting a small shift in this network's treatment ranks overall. Preliminary observations suggest that a study's size, the number of studies making a treatment comparison, and the agreement of a study's estimated treatment effect(s) with those estimated by other studies making the same comparison(s) may explain the overall robustness of treatment ranks to studies. CONCLUSIONS: Investigating robustness or sensitivity in an NMA may reveal outlying rank changes that are clinically or policy-relevant. Cohen's kappa is a useful measure that permits investigation into study characteristics that may explain varying sensitivity to individual studies. However, this study presents a framework as a proof of concept and further investigation is required to identify potential factors associated with the robustness of treatment ranks using more extensive empirical evaluations.

Investigating the impact of design characteristics on statistical efficiency within discrete choice experiments: A systematic survey.

OBJECTIVES: This study reviews simulation studies of discrete choice experiments to determine (i) how survey design features affect statistical efficiency, (ii) and to appraise their reporting quality. OUTCOMES: Statistical efficiency was measured using relative design (D-) efficiency, D-optimality, or D-error. METHODS: For this systematic survey, we searched Journal Storage (JSTOR), Since Direct, PubMed, and OVID which included a search within EMBASE. Searches were conducted up to year 2016 for simulation studies investigating the impact of DCE design features on statistical efficiency. Studies were screened and data were extracted independently and in duplicate. Results for each included study were summarized by design characteristic. Previously developed criteria for reporting quality of simulation studies were also adapted and applied to each included study. RESULTS: Of 371 potentially relevant studies, 9 were found to be eligible, with several varying in study objectives. Statistical efficiency improved when increasing the number of choice tasks or alternatives; decreasing the number of attributes, attribute levels; using an unrestricted continuous "manipulator" attribute; using model-based approaches with covariates incorporating response behaviour; using sampling approaches that incorporate previous knowledge of response behaviour; incorporating heterogeneity in a model-based design; correctly specifying Bayesian priors; minimizing parameter prior variances; and using an appropriate method to create the DCE design for the research question. The simulation studies performed well in terms of reporting quality. Improvement is needed in regards to clearly specifying study objectives, number of failures, random number generators, starting seeds, and the software used. CONCLUSION: These results identify the best approaches to structure a DCE. An investigator can manipulate design characteristics to help reduce response burden and increase statistical efficiency. Since studies varied in their objectives, conclusions were made on several design characteristics, however, the validity of each conclusion was limited. Further research should be conducted to explore all conclusions in various design settings and scenarios. Additional reviews to explore other statistical efficiency outcomes and databases can also be performed to enhance the conclusions identified from this review.

Reference interval estimation: Methodological comparison using extensive simulations and empirical data.

OBJECTIVE: To statistically compare and evaluate commonly used methods of estimating reference intervals and to determine which method is best based on characteristics of the distribution of various data sets. DESIGN AND METHODS: Three approaches for estimating reference intervals, i.e. parametric, non-parametric, and robust, were compared with simulated Gaussian and non-Gaussian data. The hierarchy of the performances of each method was examined based on bias and measures of precision. The findings of the simulation study were illustrated through real data sets. RESULTS: In all Gaussian scenarios, the parametric approach provided the least biased and most precise estimates. In non-Gaussian scenarios, no single method provided the least biased and most precise estimates for both limits of a reference interval across all sample sizes, although the non-parametric approach performed the best for most scenarios. The hierarchy of the performances of the three methods was only impacted by sample size and skewness. Differences between reference interval estimates established by the three methods were inflated by variability. CONCLUSIONS: Whenever possible, laboratories should attempt to transform data to a Gaussian distribution and use the parametric approach to obtain the most optimal reference intervals. When this is not possible, laboratories should consider sample size and skewness as factors in their choice of reference interval estimation method. The consequences of false positives or false negatives may also serve as factors in this decision.

Perceptions and experiences of a gender gap at a Canadian research institute and potential strategies to mitigate this gap: a sequential mixed-methods study.

BACKGROUND: The gender gap in academia is long-standing. Failure to ensure that our academic faculty reflect our student pool and national population deprives Canada of talent. We explored the gender distribution and perceptions of the gender gap at a Canadian university-affiliated, hospital-based research institute. METHODS: We completed a sequential mixed-methods study. In phase 1, we used the research institute's registry of scientists (1999-2014) and estimated overall prevalence of a gender gap and the gap with respect to job description (e.g., associate v. full-time) and research discipline. In phase 2, we conducted qualitative interviews to provide context for phase 1 data. Both purposive and snowball sampling were used for recruitment. RESULTS: The institute included 30.1% (n = 62) women and 69.9% (n = 144) men, indicating a 39.8% gender gap. Most full-time scientists (60.3%, n = 70) were clinicians; there were 54.2% more male than female clinician scientists. Ninety-five percent of basic scientists were men, indicating a 90.5% gap. Seven key themes emerged from 21 interviews, including perceived impact of the gender gap, factors perceived to influence the gap, recruitment trends, presence of institutional support, mentorship and suggestions to mitigate the gap. Several factors were postulated to contribute to the gender gap, including unconscious bias in hiring. INTERPRETATION: A substantial gender gap exists within this research institute. Participants identified strategies to address this gap, such as establishing transparent search processes, providing opportunities for informal networking and mentorship of female scientists and establishing institutional support for work-life balance.

An evaluation of the comparative effectiveness of geriatrician-led comprehensive geriatric assessment for improving patient and healthcare system outcomes for older adults: a protocol for a systematic review and network meta-analysis.

BACKGROUND: Comprehensive geriatric assessment (CGA) is an integrated model of care involving a geriatrician and an interdisciplinary team and can prioritize and manage complex health needs of older adults with multimorbidity. CGAs differ across healthcare settings, ranging from shared care conducted in primary care settings to specialized inpatient units in acute care. Models of care involving geriatricians vary across healthcare settings, and it is unclear which CGA model is most effective. Our objective is to conduct a systematic review and network meta-analysis (NMA) to examine the comparative effectiveness of various geriatrician-led CGAs and to identify which models improve patient and healthcare system level outcomes. METHODS: An integrated knowledge translation approach will be used and knowledge users (KUs) including patients, caregivers, geriatricians, and healthcare policymakers will be involved throughout the review. Electronic databases including MEDLINE, EMBASE, Cochrane library, and Ageline will be searched from inception to November 2016 to identify relevant studies. Randomized controlled trials of older adults (≥65 years of age) that examine geriatrician-led CGAs compared to any intervention will be included. Primary and secondary outcomes will be selected by KUs to ensure the results are relevant to their decision-making. Two reviewers will independently screen the search results, extract data, and assess risk of bias. Data will be synthesized using an NMA to allow for multiple comparisons using direct (head-to-head) as well as indirect evidence. Interventions will be ranked according to their effectiveness using surface under the cumulative ranking curve (SUCRA). DISCUSSION: As the proportion of older adults grows worldwide, the demand for specialized geriatric services that help manage complex health needs of older adults with multimorbidity will increase in many countries. Results from this systematic review and NMA will enhance decision-making and the efficient allocation of scarce geriatric resources. Moreover, active involvement of KUs throughout the review process will ensure the results are relevant to different levels of decision-making. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014014008.