Paul E. Alexander

Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis.

The impact of transfusing fresher vs older red blood cells (RBCs) on patient-important outcomes remains controversial. Two recently published large trials have provided new evidence. We summarized results of randomized trials evaluating the impact of the age of transfused RBCs. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Database for Systematic Reviews, and Cochrane CENTRAL for randomized controlled trials enrolling patients who were transfused fresher vs older RBCs and reported outcomes of death, adverse events, and infection. Independently and in duplicate, reviewers determined eligibility, risk of bias, and abstracted data. We conducted random effects meta-analyses and rated certainty (quality or confidence) of evidence using the GRADE approach. Of 12 trials that enrolled 5229 participants, 6 compared fresher RBCs with older RBCs and 6 compared fresher RBCs with current standard practice. There was little or no impact of fresher vs older RBCs on mortality (relative risk [RR], 1.04; 95% confidence interval [CI], 0.94-1.14; P = .45; I(2) = 0%, moderate certainty evidence) or on adverse events (RR, 1.02; 95% CI, 0.91-1.14; P = .74; I(2) = 0%, low certainty evidence). Fresher RBCs appeared to increase the risk of nosocomial infection (RR, 1.09; 95% CI, 1.00-1.18; P = .04; I(2) = 0%, risk difference 4.3%, low certainty evidence). Current evidence provides moderate certainty that use of fresher RBCs does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates. The existing evidence provides no support for changing practices toward fresher RBC transfusion.

Decision aids for localized prostate cancer treatment choice: Systematic review and meta-analysis.

Patients who are diagnosed with localized prostate cancer need to make critical treatment decisions that are sensitive to their values and preferences. The role of decision aids in facilitating these decisions is unknown. The authors conducted a systematic review of randomized trials of decision aids for localized prostate cancer. Teams of 2 reviewers independently identified, selected, and abstracted data from 14 eligible trials (n = 3377 men), of which 10 were conducted in North America. Of these, 11 trials compared decision aids with usual care, and 3 trials compared decision aids with other decision aids. Two trials suggested a modest positive impact on decisional regret. Results across studies varied widely for decisional conflict (4 studies), satisfaction with decision (2 studies), and knowledge (2 studies). No impact on treatment choices was observed (6 studies). In conclusion, scant evidence at high risk of bias suggests the variable impact of existing decision aids on a limited set of decisional processes and outcomes. Because current decision aids provide information but do not directly facilitate shared decision making, subsequent efforts would benefit from user‐centered design of decision aids that promote shared decision making. CA Cancer J Clin 2015;65: 239–251.

World Health Organization recommendations are often strong based on low confidence in effect estimates

OBJECTIVES Expert guideline panelists are sometimes reluctant to offer weak/conditional/contingent recommendations. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance warns against strong recommendations when confidence in effect estimates is low or very low, suggesting that such recommendations may seldom be justified. We aim to characterize the classification of strength of recommendations and confidence in estimates in World Health Organization (WHO) guidelines that used the GRADE approach and graded both strength and confidence (GRADEd). STUDY DESIGN AND SETTING We reviewed all WHO guidelines (January 2007 to December 2012), identified those that were GRADEd, and, in these, examined the classifications of strong and weak and associated confidence in estimates (high, moderate, low, and very low). RESULTS We identified 116 WHO guidelines in which 43 (37%) were GRADEd and had 456 recommendations, of which 289 (63.4%) were strong and 167 (36.6%) were conditional/weak. Of the 289 strong recommendations, 95 (33.0%) were based on evidence warranting low confidence in estimates and 65 (22.5%) on evidence warranting very low confidence in estimates (55.5% strong recommendations overall based on low or very low confidence in estimates). CONCLUSION Strong recommendations based on low or very low confidence estimates are very frequently made in WHO guidelines. Further study to determine the reasons for such high uncertainty recommendations is warranted.

Decision aids for localized prostate cancer treatment choice

Patients who are diagnosed with localized prostate cancer need to make critical treatment decisions that are sensitive to their values and preferences. The role of decision aids in facilitating these decisions is unknown. The authors conducted a systematic review of randomized trials of decision aids for localized prostate cancer. Teams of 2 reviewers independently identified, selected, and abstracted data from 14 eligible trials (n = 3377 men), of which 10 were conducted in North America. Of these, 11 trials compared decision aids with usual care, and 3 trials compared decision aids with other decision aids. Two trials suggested a modest positive impact on decisional regret. Results across studies varied widely for decisional conflict (4 studies), satisfaction with decision (2 studies), and knowledge (2 studies). No impact on treatment choices was observed (6 studies). In conclusion, scant evidence at high risk of bias suggests the variable impact of existing decision aids on a limited set of decisional processes and outcomes. Because current decision aids provide information but do not directly facilitate shared decision making, subsequent efforts would benefit from user‐centered design of decision aids that promote shared decision making. CA Cancer J Clin 2015;65: 239–251.

World Health Organization strong recommendations based on low-quality evidence (study quality) are frequent and often inconsistent with GRADE guidance

OBJECTIVES In 2007 the World Health Organization (WHO) adopted the GRADE system for development of public health guidelines. Previously we found that many strong recommendations issued by WHO are based on evidence for which there is only low or very low confidence in the estimates of effect (discordant recommendations). GRADE guidance indicates that such discordant recommendations are rarely appropriate but suggests five paradigmatic situations in which discordant recommendations may be warranted. We sought to provide insight into the many discordant recommendations in WHO guidelines. STUDY DESIGN AND SETTING We examined all guidelines that used the GRADE method and were approved by the WHO Guideline Review Committee between 2007 and 2012. Teams of reviewers independently abstracted data from eligible guidelines and classified recommendations either into one of the five paradigms for appropriately-formulated discordant recommendations or into three additional categories in which discordant recommendations were inconsistent with GRADE guidance: 1) the evidence warranted moderate or high confidence (a misclassification of evidence) rather than low or very low confidence; 2) good practice statements; or 3) uncertainty in the estimates of effect would best lead to a conditional (weak) recommendation. RESULTS The 33 eligible guidelines included 160 discordant recommendations, of which 98 (61.3%) addressed drug interventions and 132 (82.5%) provided some rationale (though not entirely explicit at times) for the strong recommendation. Of 160 discordant recommendations, 25 (15.6%) were judged consistent with one of the five paradigms for appropriate recommendations; 33 (21%) were based on evidence warranting moderate or high confidence in the estimates of effect; 29 (18%) were good practice statements; and 73 (46%) warranted a conditional, rather than a strong recommendation. CONCLUSION WHO discordant recommendations are often inconsistent with GRADE guidance, possibly threatening the integrity of the process. Further training in GRADE methods for WHO guideline development group members may be necessary, along with further research on what motivates the formulation of such recommendations.

Is H9N2 Avian Influenza Virus a Pandemic Potential

To the Editor: H1N1 and H3N2 influenza virus subtypes continue to cause human disease (1,2), while avian influenza A H5 and H7 subtypes spread globally among birds with limited an inefficient transmission to humans (3,4). Results from recent ferret research on the H9N2 subtype has demonstrated an increased theoretical threat to humans from the potential emergence of novel subtypes of avian influenza. In North America, there is no evidence of fixed lineages of the H9N2 avian influenza virus in land-based poultry; it is found in wild ducks and shore birds (5). In contrast, H9N2 remains endemic across Asia, mainly limited to outbreaks in domestic land-based poultry, but overshadowed as a pandemic threat by H5N1 bird flu, which has spread from Asia into Africa and Europe (6–9). However, there is evidence of interspecies transmission of H9N2 from land-based poultry to mammals, such as pigs and swine (10–13). Further evidence of an expanded mammalian host range includes efficient replication of H9N2 in mice without adaptation (14). H9N2 has already caused mild respiratory disease in humans in Hong Kong and mainland China in 1999 and 2003 (10,13,15,16). The six genes encoding the internal components of the H9N2 virus are similar to those found in a previous 1997 outbreak of H5N1 that caused several human deaths in Hong Kong (15). Furthermore, circulating H9N2 strains show human-like receptor specificity with amino acid leucine at position 226 at the receptor-binding site of human airway epithelial cells cultured in vitro (17). H9N2 isolated from live bird markets in Hong Kong possessed receptor specificity similar to human H3N2 viruses (18) and mutations similar to human H2N2 and H3N2 viruses, so the glycoproteins of the Hong Kong H9N2 viruses may potentially promote human infection. In a ferret model of transmission (9), the H9N2 avian reassortment subtype appears to be evolving. The H9N2 virus replicates in the respiratory tract of ferrets and can spread to noninfected ferrets (9). The amino acid leucine residue located at position 226 in the hemagglutinin receptor-binding site (instead of glutamine), plays a key role in human virus-like receptor specificity, and promotes transmission of the H9N2 virus in ferrets. Airborne transmission has not been detected. Mixing the H9N2 viral genes containing the surface glycoprotein and the six internal genes of a human H3N2 virus resulted in increased transmissibility. The model and reassortment mixing results raises concern about viral evolution as well as efficient pandemic transmission, and suggests that the H9N2 avian virus could be of pandemic importance (19). To conclude that H9N2 is the next human pandemic strain is premature at this time given the unfolding evidence. Yet, the possibility for competent nonavian intermediate reassorters generating novel and virulent pandemic strains of H9N2 (or other avain influenza strains) has increased given the recent raccoon influenza transmission findings (20). Additional study and timely surveillance of H9N2 is needed to identify any increments in viral adaptation to human beings. Studies should consider the widespread prevalence of the H9N2 virus in poultry, and co-circulation and mixing of avian H9N2 with human H3N2, H5, H7 and other avian and mammalian viruses.

Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis

This article describes conceptual advances of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group guidance to evaluate the certainty of evidence (confidence in evidence, quality of evidence) from network meta-analysis (NMA). Application of the original GRADE guidance, published in 2014, in a number of NMAs has resulted in advances that strengthen its conceptual basis and make the process more efficient. This guidance will be useful for systematic review authors who aim to assess the certainty of all pairwise comparisons from an NMA and who are familiar with the basic concepts of NMA and the traditional GRADE approach for pairwise meta-analysis. Two principles of the original GRADE NMA guidance are that we need to rate the certainty of the evidence for each pairwise comparison within a network separately and that in doing so we need to consider both the direct and indirect evidence. We present, discuss, and illustrate four conceptual advances: (1) consideration of imprecision is not necessary when rating the direct and indirect estimates to inform the rating of NMA estimates, (2) there is no need to rate the indirect evidence when the certainty of the direct evidence is high and the contribution of the direct evidence to the network estimate is at least as great as that of the indirect evidence, (3) we should not trust a statistical test of global incoherence of the network to assess incoherence at the pairwise comparison level, and (4) in the presence of incoherence between direct and indirect evidence, the certainty of the evidence of each estimate can help decide which estimate to believe.

A number of factors explain why WHO guideline developers make strong recommendations inconsistent with GRADE guidance

OBJECTIVE Many strong recommendations issued by the World Health Organization (WHO) are based on low- or very low-quality (low certainty) evidence (discordant recommendations). Many such discordant recommendations are inconsistent with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance. We sought to understand why WHO makes discordant recommendations inconsistent with GRADE guidance. STUDY DESIGN AND SETTING We interviewed panel members involved in guidelines approved by WHO (2007-2012) that included discordant recommendations. Interviews, recorded and transcribed, focused on use of GRADE including the reasoning underlying, and factors contributing to, discordant recommendations. RESULTS Four themes emerged: strengths of GRADE, challenges and barriers to GRADE, strategies to improve GRADE application, and explanations for discordant recommendations. Reasons for discordant recommendations included skepticism about the value of making conditional recommendations; political considerations; high certainty in benefits (sometimes warranted, sometimes not) despite assessing evidence as low certainty; and concerns that conditional recommendations will be ignored. CONCLUSION WHO panelists make discordant recommendations inconsistent with GRADE guidance for reasons that include limitations in their understanding of GRADE. Ensuring optimal application of GRADE at WHO and elsewhere likely requires selecting panelists who have a commitment to GRADE principles, additional training of panelists, and formal processes to maximize adherence to GRADE principles.

Systematic review and network meta-analysis of interventions for fibromyalgia: a protocol

BackgroundFibromyalgia is associated with substantial socioeconomic loss and, despite considerable research including numerous randomized controlled trials (RCTs) and systematic reviews, there exists uncertainty regarding what treatments are effective. No review has evaluated all interventional studies for fibromyalgia, which limits attempts to make inferences regarding the relative effectiveness of treatments.Methods/designWe will conduct a network meta-analysis of all RCTs evaluating therapies for fibromyalgia to determine which therapies show evidence of effectiveness, and the relative effectiveness of these treatments. We will acquire eligible studies through a systematic search of CINAHL, EMBASE, MEDLINE, AMED, HealthSTAR, PsychINFO, PapersFirst, ProceedingsFirst, and the Cochrane Central Registry of Controlled Trials. Eligible studies will randomly allocate patients presenting with fibromyalgia or a related condition to an intervention or a control. Teams of reviewers will, independently and in duplicate, screen titles and abstracts and complete full text reviews to determine eligibility, and subsequently perform data abstraction and assess risk of bias of eligible trials. We will conduct meta-analyses to establish the effect of all reported therapies on patient-important outcomes when possible. To assess relative effects of treatments, we will construct a random effects model within the Bayesian framework using Markov chain Monte Carlo methods.DiscussionOur review will be the first to evaluate all treatments for fibromyalgia, provide relative effectiveness of treatments, and prioritize patient-important outcomes with a focus on functional gains. Our review will facilitate evidence-based management of patients with fibromyalgia, identify key areas for future research, and provide a framework for conducting large systematic reviews involving indirect comparisons.

Mortality outcomes in patients transfused with fresher versus older red blood cells: a meta-analysis

Among transfused patients, the effect of the duration of red blood cell storage on mortality remains unclear. This study aims to compare the mortality of patients who were transfused with fresher versus older red blood cells.