Evidence Foundation scholar spotlight: Georgios Schoretsanitis

Last fall, Dr. Georgios Schoretsanitis attended the 13th (and first-ever virtual) GRADE guideline development workshop as a scholar of the Evidence Foundation. As such, he presented to the rest of the workshop attendees on his work developing guidelines for therapeutic drug monitoring to optimize and tailor treatment for psychotherapeutic medications. Beginning in 2017, a series of recommendations for reference ranges for two commonly prescribed antipsychotic medications was developed, followed this year by an international joint consensus statement on blood levels to optimize antipsychotic treatment in clinical practice.

Dr. Schoretsanitis now has an exciting update on his project.

"My main research interest is therapeutic drug monitoring, also known as TDM, which refers to the quantification and interpretation of medication levels in the blood (plasma or serum) of the patient treated with psychotropic agents," says Dr. Schoretsanitis. "The aim of TDM in clinical practice is to improve treatment response and safety outcomes. Apart from analyzing TDM clinical routine data, I have also been working as a member of the TDM taskforce of the German Association of Neuropsychopharmacology and Phaarmacopsychiatry (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmacopsychiatrie; AGNP) involved in systematic reviews of TDM literature, which provide so-called therapeutic reference ranges for medication levels. These ranges may orient clinicians during dose selection. Attending the virtual GRADE workshop in October 2020 provided me much of inspiration, but also knowledge of well-established methodological tools for the assessment of quality of evidence.

Hereafter, in the TDM task force of AGNP, we adopted a GRADE-oriented approach in assessing TDM literature as we are reviewing new TDM evidence on commonly prescribed antipsychotics under the supervision of Prof. Gerhard Gründer, Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. This type of approach is more standardized and follows GRADE guidelines. Ultimately, this work will enhance methodological rigidity for the next Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology [last update 2018; Hiemke et al, Pharmacopsychiatry]. I strongly encourage researchers involved in systematic reviews or assessment of evidence quality to attend the GRADE workshop which enables a major upgrade of related skills and knowledge."

Stay tuned for future updates from other past Evidence Foundation scholars like Dr. Schoretsanitis and the exciting work they are doing to improve the application of GRADE methodology and evidence-based medicine.

If you are interested in learning more about GRADE and attending the workshop as a scholarship recipient, applications for our upcoming virtual workshop in October are now open. The deadline to apply is July 31, 2021. Details can be found here. 

The Systematic Survey Behind a Collection of Minimal Important Differences (MIDs) Across the Patient-Reported Outcome Literature

Patient-reported outcome measures, or PROMs, allow clinicians and researchers to directly elicit information about treatments that are important to patients, such as side effects or improvements in pain, function, or quality of life. In order to interpret changes in PROMs relative to a clinical recommendation, however, a minimal important difference (MID) - or the smallest possible change in the outcome that would mandate a change in the patient's management - must be determined.

Luckily, a wealth of published studies exist to provide a library of MIDs for a wide range of outcomes, and recently, a review published by Carrasco-Labra and colleagues synthesized these works together. The study included any empirical reports of MIDs in adolescents or adults that used an anchor-based approach, in which MIDs are based on an observed change related to an external criterion rather than the distribution of a particular patient sample. As such, anchor-based MIDs tend to be more directly applicable across patient populations. Ultimately, a collection of 585 studies reporting on 5,324 MID estimates across 526 distinct PROMs was presented.

About two-thirds (66%) collected MIDs related to patients' improvement, whereas about one-third (31%) addressed MIDs related to worsening or assumed the MIDs for improvement or worsening would be the same. Most (88%) were based on a longitudinal design in which patients' reported outcomes and satisfaction were measured at multiple timepoints. The most common types of anchors used were global ratings of change (59%), change in disease-related outcome (23%), and comparison with another group (11%), whereas the most common sources of anchor information were self-report (83%) proxy-reported (9%) and laboratory data (3%). 

MIDs are essential in interpreting the magnitude of an effect from a study or systematic review of evidence, especially when assessing imprecision as part of GRADE. They can also allow researchers to conduct "responder analyses" based on subsets of patients who experience a change in an outcome beyond a given MID. Finally, reporting mean differences in units of MIDs as part of a systematic review can standardize interpretation of an effect size in a way that may be less problematic to interpret than a traditional standardized mean difference (SMD).

The work corresponds to PROMID, a project to develop an inventory of MIDs across the literature, which can be accessed at https://promid.mcmaster.ca/. 

Carrasco-Labra A, Devji T, Qasim A, et al. (2021). Minimal important difference estimates for patient-reported outcomes: A systematic survey. J Clin Epidemiol 133:61-71.

Manuscript available at the publisher's website here. 

Reliability of Risk of Bias Assessments of Non-randomized Studies Improves After Customized Training

We previously reported on a paper published in 2020 assessing the inter-rater reliability (IRR) and inter-consensus reliability (ICR) of the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool, developed in 2016, and the Risk of Bias instrument for NRS of Exposures (ROB-NRSE) tool, developed in 2018. This paper found that reliability generally tended to be poor for these tools, while risk of bias assessments took evaluators, on average, 48 minutes for the ROBINS-I tool and almost 37 minutes for the ROB-NRSE.

Now, a new publication from the same group has examined the effect of training on the reliability of these tools. An international team of reviewers with a median of 5 years of experience with risk of bias assessment first applied the ROBINS-I and ROB-NRSE tools to a list of 44 non-randomized studies of interventions and exposures, respectively, using only the 53 pages of publicly available guidance. Then, the reviewers received an abridged and customized training document which was tailored specifically to the topic area of the reviews, included simplified guidance for assessing risk of bias, and also provided additional guidance related to more advanced concepts. The reviewers then re-assessed the studies' risk of bias after a several-weeks-long wash-out period.

Changes in the inter-rater reliability (IRR) for the ROBINS-I (top) and ROB-NRSE tools (bottom) from before and after a customized training intervention.

The training intervention improved the IRR of the ROBINS-I tool, generally improving the range of within-domain reliability while the reliability of the overall bias rating improved from "poor" to "fair." Meanwhile, the ICR improved substantially, with the overall rating's reliability improving from "poor" to "near perfect." Improvements were also observed after training in the application of the ROB-NRSE tool, with IRR of the overall bias improving significantly from "slight" to "near perfect" while its ICR improved from "poor" to "near perfect." For both tools, the pre-to-post-intervention correlations between reviewers' scores were poor, suggesting that the training did have an impact on these measures independent of a simple learning effect. While customized training was associated with a decrease in evaluator burden for the ROBINS-I tool, this did not hold true for the ROB-NRSE.

The findings of this analysis suggest that the use of a customized, shortened guidance tool specifically tailored to the topical content of a review, including simplified guidance for decision-making within each domain, can improve the reliability of resulting risk of bias assessments. The authors suggest that future reviewers create such guidance based on the specific needs and considerations of their topic area, and publish these tools along with the review.

Jeyaraman MM, Robson RC, Copstein L et al. (2021). Customized guidance/training improved the psychometric properties of methodologically rigorous risk of bias instruments for non-randomized studies. J Clin Epidemiol, in-press.

Manuscript available here. 

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 figure above shows the frequency of languages of the excluded reviews examined.

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. 

In Studies of Patients at High Risk of Death, More Explicit Reporting of Functional Outcomes is Needed

Randomized controlled trials examining the effects of an intervention in patients with a high risk of death will often also include functional outcomes - such as quality of life, cognition, or physical disability. However, the death of patients before these outcomes can be assessed (also known as "truncation due to death") can confound the results of a "survivors-only" analysis, especially if mortality rates are higher in certain groups than others. 

A new methodology review of studies published within 5 high-impact general medical journals from 2014 to 2019 provides insight into this phenomenon and suggestions for improving how functional outcomes are handled. To be eligible for the review, a study needed to be a randomized controlled trial (RCT) with a mortality rate of at least 10% in one arm and to report at least one functional outcome in addition to mortality. The authors recorded the outcomes analyzed, the type of statistical analyses used, and the sample population of each of the 434 included studies. For most (351, or 79%) of these, function was a secondary outcome, while it was a primary outcome for 91 (21%) of them.

Only one-quarter (25%) of the functional outcomes within the studies that examined them as secondary outcomes used an approach that included all randomized patients (intention-to-treat); for the studies for which functional outcomes were the primary outcomes analyzed, this proportion was 60%.

The authors provide suggestions for best ways to handle and report data in these studies:

• 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. 

Colantuoni E, Li X, Hashem MD et al. (2021). A structured methodology review showed analyses of functional outcomes are frequently limited to "survivors only" in trials enrolling patients at high risk of death. J Clin Epidemiol (e-pub ahead of print).

Manuscript available here.

Digging Deeper: 5 Ways to Help Guide Decision-Making When Research Evidence is "Insufficient"

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.

Through this approach, the workgroup identified five key strategies for dealing with the challenge of insufficient evidence:

1. Reconsider eligible study designs: broaden your search to capture a wider variety of published evidence, such as cohort or case studies.
2. 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.
3. 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.
4. 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.
5. Incorporate health system data: "real-world" evidence such as electronic health records and registries can supplement more mechanistic or explanatory RCTs.

Some of these challenges can be more efficiently addressed up-front, before the scoping of a new review even begins. For instance, identifying topic experts and stakeholders who are familiar with the quantity and quality of available evidence can help a group foresee potential gaps and plan for the need to broaden the scope. Care should be taken to identify the outcomes that are of critical importance to patients, and through this lens, develop strategies and criteria within the protocol that will best meet the needs of the review while tapping into as much evidence as possible. Finally, researchers should avoid using the term "insufficient" when describing the evidence, and instead explicitly state that no eligible studies or types of evidence were available.

Murad MH, Chang SM, Fiordalisi CV, et al. (2021). Improving the utility of evidence synthesis for decisionmakers in the face of insufficient evidence. J Clin Epidemiol, ahead-of-print. 

Manuscript available from publisher's website here.

New Review of Pragmatic Trials Reveals Insights, Identifies Gaps

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).