Friday, May 14, 2021
Reliability of Risk of Bias Assessments of Non-randomized Studies Improves After Customized Training
Tuesday, May 4, 2021
Restricting Systematic Search to English-only is a Viable Shortcut in Most, but Perhaps Not All Topics in Medicine
In the limitations sections of systematic reviews on any topic, it is not uncommon for the authors to discuss how language limitations within their search may have restricted the breadth of evidence presented. For instance, if the reviewers speak only English, the review is likely limited to publications and journals in that language. But how much of a difference does such a limitation make in terms of the overall conclusions of a systematic review? According to a new paper in the Journal of Clinical Epidemiology, probably not much - but it may depend on the specific topic of medicine under investigation.
While other methods reviews have previously examined this question, Dobrescu and colleagues extended the range of topics to methods reviews that included systematic reviews within the realm of complementary and alternative medicine, yielding four reviews previously unexamined by prior studies. Specifically, the authors looked for methods reviews comparing the restriction of literature searches to English-only versus unrestricted searches and whose primary outcomes compared differences in treatment effect estimates, certainty of evidence ratings, or conclusions based on the language restrictions enforced.
The search yielded eight studies investigating the impact of language restrictions in anywhere from 9 to 147 systematic reviews in medicine. Overall, the exclusion of non-English articles had a greater impact on estimates of treatment effects and the statistical significance of findings in reviews of complementary and alternative medicine versus conventional medicine topics. Most commonly, the exclusion of non-English studies led to a loss of statistical significance in these topic areas.
Overall, the methods studies examined found that the exclusion of non-English studies of conventional medicine topics led to small to moderate changes in the estimate of effect; however, exclusion of non-English studies shrank the observed effect size in complementary and alternative medicine topics by 63 percent. Two studies examined whether language restricted influenced authors' overall conclusions, generally finding no effect.
The authors conclude that when it comes to systematic reviews of conventional medicine topics, their findings are in line with those of previous methods studies which demonstrate little to no effect of language restrictions and suggest that restricting a search to English-only should not greatly impact the findings or conclusions of a review. However, the effect appears greater in the realm of complementary and alternative medicine, perhaps due to the greater proportion of non-English studies published in this field. Thus, systematic reviewers attempting to synthesize the evidence on an alternative medicine topic should be cognizant of their choices regarding language restriction and the potential implications they may have on their ultimate findings.
Dobrescu A, Nussbaumer SB, Klerings I et al. (2021). Restricting evidence syntheses of interventions to English-language publications is a viable methodological shortcut for most medical topics: A systematic review: Excluding English-language publications a valid shortcut. J Clin Epidemiol, epub ahead of print.
Manuscript available from publisher's website here.
Wednesday, April 21, 2021
In Studies of Patients at High Risk of Death, More Explicit Reporting of Functional Outcomes is Needed
- In the methods rather than only in tables or supplementary material, explicitly state the sample population from which the functional outcomes were drawn, whether it's survivors-only or another type of analysis.
- If a survivors-only analysis is used, the authors should report the baseline characteristics between the groups analyzed and transparently discuss this as a limitation within the discussion section.
- If all randomized participants are analyzed regardless of mortality, authors should report the assumptions upon which these analyses are based; for instance, if death is one outcome ranked among others in a worst-rank analysis, the justification for the ranking of outcomes should be discussed in the methods, and the implications of these decisions included in the discussion section.
Thursday, April 8, 2021
A key tenet underlying the GRADE framework is that the certainty of available research evidence is a key factor to be considered in the course of clinical decision-making. But what if little to no published research exists off of which to base a recommendation? At the end of the day, clinicians, patients, policymakers, and others will still need to make a decision, and will look to a guideline for direction. Thankfully, there are other options to pursue within the context of a systematic review or guideline that ensures that as much of the available evidence is presented as possible, although it may be from less traditional or direct sources.
A new project conducted by the Evidence-based Practice Center (EPC) Program of the Agency for Healthcare Research and Quality (AHRQ) developed guidance for supplementing a review of evidence when the available research evidence is sparse or insufficient. This guidance was based on a three-pronged approach, including:
- a literature review of articles that have defined and dealt with insufficient evidence,
- a convenience sample of recent systematic reviews conducted by EPCs that included at least one outcome for which the evidence was rated as insufficient, and
- an audit of technical briefs from the EPCs, which tend to be developed when a given topic is expected to yield little to no published evidence and which often contain supplementary sources of information such as grey literature and expert interviews.
- Reconsider eligible study designs: broaden your search to capture a wider variety of published evidence, such as cohort or case studies.
- Summarize evidence outside the prespecified review parameters: use indirect evidence that does not perfectly match the PICO of your topic in order to better contextualize the decision being presented.
- Summarize evidence on contextual factors (factors other than benefits/harms): these include key aspects of the GRADE Evidence-to-Decision framework, such as patient values and preferences and the acceptability, feasibility, and cost-effectiveness of a given intervention.
- Consider modeling if appropriate, and if expertise is available: if possible, certain types of modeling can help fill in the gaps and make useful predictions for outcomes in lieu of real-life research.
- Incorporate health system data: "real-world" evidence such as electronic health records and registries can supplement more mechanistic or explanatory RCTs.
Friday, April 2, 2021
As opposed to an "explanatory" or "mechanistic" randomized controlled trial (RCT), which seeks to examine the effect of an intervention under tightly controlled circumstances, "pragmatic" or "naturalistic" trials study interventions and their outcomes when used in more real-world, generalizable settings. One example of such a study might include the use of registry data to examine interventions and outcomes as they occur in the "real world" of patient care. However, there are currently few standards for identifying, reporting, and discussing the results of such "pragmatic RCTs." A new paper by Nicholls and colleagues aims to provide an overview of the current landscape of this methodological genre.
The authors searched for and synthesized 4,337 trials using keywords such as "pragmatic," "real world," "registry based," and "comparative effectiveness" to better map an understanding of how pragmatic trials are presented in the RCT literature. Overall, only about 22% (964) of these trials were identified as "pragmatic" RCTs in the title, abstract, or full text; about half of these (55%) used this term in the title or abstract, while the remaining 45% described the work as a pragmatic trial only in the full text.
About 78.1% (3,368) of the trials indicated that they were registered. However, only about 6% were indexed in PubMed as a pragmatic trial, and only 0.5% were labeled with the MeSH topic of Pragmatic Clinical Trial. The target enrollment of pragmatic trials was a median of 440 participants within an interquartile range (IQR) of 244 to 1,200; the actual achieved accrual was 414 (IQR: 216 - 1,147). The largest trial included 933,789 participants; the smallest enrolled 60.
Overall, pragmatic trials were more likely to be centered in North America and Europe and to be funded by non-industry sources. Behavioral, rather than drug or device-based, interventions were most common in these trials. Not infrequently, the trials were mislabeled or contained erroneous data in their registration information. The fact that only about half of the sample were clearly labeled as "pragmatic" may mean that these trials may go undetected with less sensitive search mechanisms than the authors used.
Authors of pragmatic trials can improve the quality of the field by clearly labelling their work as such and by registering their trials and ensuring that registered data are accurate and up-to-date. The authors also suggest that taking a broader view of what constitutes a "pragmatic RCT" also generates questions regarding proper ethical standards when research is conducted on a large scale with multiple lines of responsibility. Finally, the mechanisms used to obtain consent in these trials should be further examined in light of the finding that many pragmatic trials fail to achieve goals set for participant enrollment.
Manuscript available from publisher's web site here.
Nicholls SG, Carroll K, Hey SP, et al. (2021). A review of pragmatic trials found a high degree of diversity in design and scope, deficiencies in reporting and trial registry data, and poor indexing. J Clin Epidemiol (ahead of print).
Monday, March 15, 2021
While the use of blinding is a hallmark of placebo-controlled trials, whether the blinding was successful - i.e., whether or not participants were able to figure out the treatment condition to which they have been assigned - isn't always tested, nor are the results of these tests always reported. The measurement of the success of blinding in trials is controversial and not uniformly used, and the item has been dropped from subsequent versions of the CONSORT reporting items for trials. According to a recent discussion of the pros and cons to measuring the success of blinding, only between 2-24% of trials perform or report these types of tests.
As Webster and colleagues explain, the benefits to measuring the success of blinding are as follows:
- the success (or failure) of blinding in a placebo-controlled trial can introduce a source of bias that affects the results.
- while the effect of blinding itself may be small, these small effects could still result in changes to policy or practice
- there are documented instances in which the failure to properly blind (for instance, providing participants with a sour-tasting Vitamin C condition versus a sweet lactose "placebo") led to an observed effect (for instance, on preventing or treating the common cold) whereas there was no effect in the subgroup of participants who were successfully blinded.
- At times, a break in blinding can lead to conclusions in the opposite direction. For instance, physicians who are unblinded may assume that the patients with better outcomes received a drug widely supposed to be "superior," when in fact, the opposite occurred.
- In some cases, a treatment with dramatically superior results can result in unblinding, even when the treatment conditions were identical - but that doesn't necessarily mean the blinding was a failure or could have been prevented, given the dramatic differences in outcomes.
- If the measurement of blinding is performed at the wrong time - such as before the completion of the trial - participants may become suspicious and this in itself could potentially confound treatment effects.
Tuesday, March 9, 2021
To guide the formulation of clinical recommendations, GRADE relies on the use of direct or, if necessary, indirect evidence from peer-reviewed publications as well as the gray literature. However, in some cases, no such evidence may be found even after an extensive search has been conducted. A new paper - part of the informal GRADE Notes series in the Journal of Clinical Epidemiology - relays the results of piloting an "expert evidence" approach and provides key suggestions when using it.
As opposed to simply asking the panel members of a guideline to base their recommendations off of informal opinion, the expert evidence approach systematizes this process by eliciting the extent of their experience with certain clinical scenarios through quantitative survey methods. In this example, at least 50% of the panel members were free of conflicts of interest, with various countries and specialties represented. While members were not required to base their answers off of patient charts, the authors suggest that this can be used to further increase the rigor of the survey.
As a result of the survey, the recommendations put forward reflected a cumulative 12,000 cases of experience. Because the members felt that at least some recommendation was necessary to help guide care - where the alternative would be to provide no recommendation at all - the guideline helped to fill a gap while indicating the current lack of high-quality published evidence for several clinical questions, which may help guide the production of higher-quality evidence and recommendations in the future. Importantly, by utilizing a survey approach to facilitate the formulation of recommendations, the authors note that it avoided the pitfall of "consensus-based" approaches to guideline development which can often manifest as simply reflecting the opinions of those with the loudest voices.
Mustafa RA, Cuello Garcia CA, Bhatt M, Riva JJ, Vesely S, Wiercioch W, ... & HJ Schünemann. (2021). How to use GRADE when there is "no" evidence? A case study of the expert evidence approach. J Clin Epidemiol, in-press.
Manuscript available from the publisher's website here.