Is Your "Gold Standard" Truly Gold? A Living Review Exposes 67 Flaws in Systematic Reviews

 Systematic reviews and meta-analysis are often referred to as the ‘gold standard’ of evidence, often trusted to guide clinical guidelines and major healthcare decisions. With so much weighing on the accuracy of systemic review, what would happen if the review itself had cracks? 
A living systematic review published in the Journal of Clinical Epidemiology critically reviewed 485 articles published since 2000, and identified 67 problems that can jeopardize the reliability and validity of these evidence syntheses.

Lesley Uttley and her team categorized these 67 problems into four main areas:

1. Comprehensive: Is all relevant evidence included?

2. Rigorous: Were appropriate methods used

3. Transparent: Can it be reproduced?

4. Objective: Is the process fair and unbiased?

—

Lesley’s reviews should be looked at as a self-check to ensure the validity of your systematic review isn’t knowingly compromised. Before submission, ask: 

• Have we involved an information specialist? 

• Have we pre-specified and justified all analyses? 

• Have we explicitly managed and declared conflicts of interest? 

• Have we considered equity? 

For readers and users of systematic reviews, try to be more skeptical and critically appraise the work before you quote. For a more involved approach:

Ask Critical Questions Based on the Four Domains:

• Comprehensiveness: Does the search strategy seem thorough? Did they look in the right places (databases, grey literature, overly stringent inclusion criteria leading to multiple updates later on) for all relevant evidence?

• Rigor: Have they properly handled study synthesis, quality and heterogeneity? The Assessing the Methodological Quality of Systematic Reviews (AMSTAR) checklist is helpful here.

• Transparency: Can you trace their steps? Is there a protocol you can consult? Is it unclear why certain studies were excluded?

• Objectivity: Are there involved experts on the team that share knowledge throughout the process? Are declared conflicts of interest properly managed?

Change Your Appraisal Mindset:

The most reliable review isn't necessarily the one with the most exciting finding, it's the one whose process you can best understand and trust. Use the four domains as your critical appraisal lens to identify potential weaknesses before applying the results to practice.

References

Uttley, Lesley et al. “The Problems with Systematic Reviews: A Living Systematic Review.” Journal of Clinical Epidemiology 156 (2023): 30–41. Manuscript available at the publisher's website here.

https://www.jclinepi.com/article/S0895-4356(23)00011-2/fulltext 

Uttley, L., Weng, Y., & Falzon, L. (2025). Yet another problem with systematic reviews: a living review update. Journal of Clinical Epidemiology 177: Article 111608. https://doi.org/10.1016/j.jclinepi.2024.111608

Manuscript available at the publisher's website here.

https://www.jclinepi.com/article/S0895-4356(24)00364-0/fulltext

Fall 2025 Scholars Propose Innovative Projects in Cancer Care and Global GRADE Dissemination

Recently, the U.S. GRADE Network and Evidence Foundation had the privilege of welcoming three new scholars to the fall 2025 virtual GRADE Guideline Development Workshop. Scholars hailed from around the world, from the U.S. to Pakistan and Germany. 

Alexander Brooks, a Ph.D. candidate in exercise science at the University of South Carolina, presented a systematic review project in development to assess the long-term effectiveness of exercise interventions in cancer survivors. "Despite the growing number of clinical trials and guidelines in this area," says Brooks, "few systematic reviews have applied structured approaches to assess the certainty of the evidence underpinning these collective recommendations." Brooks' project directly addresses this gap in the literature while examining the trajectory of health and fitness markers in this population in the short- and long-term period after cancer treatment.

Attending the GRADE workshop "strengthened my ability to critically evaluate research and better understand how evidence is synthesized to inform recommendations," said Brooks. "The hands-on exercises were particularly valuable, and I found the workshop directly applicable to my own work."

Dr. Anna-Sophie Strauss, a resident physician at University Hospital Ulm in Germany and a Cochrane Urology review author, discussed her current review of the diagnostic test accuracy of prostate-specific membrane antigen (PSMA) imaging for the staging of primary prostate cancer. The aim of this review is to inform evidence-based guidelines for this testing strategy, ultimately "supporting more informed and unbiased decision-making in urological healthcare."

"Taking part in the GRADE Guideline Development Workshop improved my understanding of how structured evidence appraisal can be used to create transparent, patient-centered recommendations," said Strauss. "I also appreciated the opportunity to exchange global perspectives, which demonstrated how rigorous methods such as GRADE can be adapted to different clinical and health system contexts." 

Finally, Dr. Muhammad Tayyab Qureshi presented from Pakistan. A House Officer in the Pakistan Air Force Hospital Islamabad, Dr. Qureshi discussed the need for the dissemination of locally relevant guidelines in Lower- and Middle-Income Countries such as Pakistan. These efforts, he believes, will strengthen "health systems through practical, evidence-informed solutions that lead to measurable improvements in health outcomes and resource use."

The training provided in the three-day GRADE workshop will allow the scholars to apply the GRADE framework to the certainty and evidence assessment and formulation of recommendations within their specific projects. 

Interested in becoming a scholar? Applications to join us for the spring 2026 workshop in Kansas City, Missouri, May 18-20, 2026, close Saturday, January 31. See application details at evidencefoundation.org/scholarships.html.

2021 Evidence Foundation Scholar Receives Health Equity Travel Scholarship

The Evidence Foundation is proud to announce that spring 2021 GRADE Workshop Scholar Ifeoluwa Babatunde, Pharm.D, MS, received the 2025 Encoding Health Equity Summit Travel Scholarship for Patients and Emerging Leaders, an opportunity made possible by Doris Duke Foundation and the Council of Medical Specialty Societies (CMSS). 

About her experience at the summit, Babatunde shared,

"The Encoding Equity conference was an enriching experience for me. I found it quite inspiring to hear about the diverse initiatives and research projects geared towards achieving health equity. Hearing from biomedical researchers, clinicians, public health providers, guideline developers, and medical societies truly showcased the depth of work in this field.

"My personal takeaway from the conference was on the power of collaboration. Successfully achieving the central goal of health equity integration would require all stakeholders, from providers & researchers to members of the very communities we aim to impact, actively sharing their perspectives. By engaging in consistent mutual learning, we can inspire innovation and translate our findings to actionable change across the entire medical ecosystem.

"As someone in guideline development, I particularly resonated with the work being done on pioneering a 'Population Conscious Analysis' approach to handling race and ethnicity as a variable in biomedical research. This innovation has me very optimistic about the positive impact it will have on new and existing quality appraisal tools being used in evidence synthesis.

"Lastly, I enjoyed engaging in discussions with poster presenters working on projects closely aligned with that of my team. Specifically, those focused on creating a race-conscious framework for for guideline development. These discussions reinforced the significant impact of the work we are engaged in."

Open the doors to opportunity:

Interested in contributing to the future of evidence-based medicine? Become an Evidence Foundation Scholar and attend our upcoming virtual fall workshop (October 29-31, 2025) for free. Application close August 31, 2025. See evidencefoundation.org/scholarships.html 

for application details.

Latest Evidence Foundation Scholar Tackles Project to Create New Quality Assessment Tool for Prevalence Studies

Prevalence studies inform understanding of an individual's baseline risk for a medical or health condition as well as the burden of the disease and the characteristics of a given target population. Meanwhile, estimates of the the absolute risk, taken from prevalence data, informs the development of evidence-based guidelines. But how can one tell if the data on prevalence are trustworthy or seriously biased?

There currently exists no widely agreed-upon tool to assess the risk of bias within studies of prevalence analogous to the Cochrane RoB 2.0 tool for randomized controlled trials or QUADAS-2 for studies of diagnostic test accuracy. Additionally, the assessment of a prevalence study comes with its own challenges, as it requires assessment of population selection, condition treatment, and analysis.

Dr. Ali Choaib, a post-doctoral research fellow in the Evidence-based Practice and Impact Center at the University of Kansas Medical Center, discussed this gap and his proposed project to address it as part of his presentation as the spring 2025 Evidence Foundation scholarship recipient.

At the GRADE Guideline Development Workshop held in Arlington, Virginia, last month, Dr. Choaib presented his work in systematically reviewing and thematically analyzing all existing tools to assess risk of bias in prevalence studies. Choaib and his team identified four major conceptual domains shared across the existing tools: study population, sampling, and setting; case/condition definition and measurement; statistical analysis; and other (e.g., conflicts of interest and missing data).

Next, Choaib's team will work to develop and receive iterative feedback on a new tool that assesses all critical domains while taking care not to include items or questions that are not specifically related to bias, such as those assessing reporting quality.

About his experience of the workshop, Choaib said, 

"The workshop was a perfect opportunity to learn, network, and collaborate with experts. Topics were dynamic and sessions tailored to individuals at all stages of the guideline development process from researchers to admins. I’m honored to have received the scholarship and to have contributed to discussions that expanded my knowledge and understanding of the guideline development process overall and with regards to diagnostic test accuracy specifically."

Choaib has additionally received the Encoding Health Equity Summit 2025 Travel Scholarship Program for Patients and Emerging Leaders. This scholarship, which is made possible with support from the Doris Duke Foundation, the Council of Medical Specialty Societies (CMSS), allowed him to attend the 2025 Encoding Health Equity Summit. This year's theme was "From Evidence to Impact."

"Encoding Health Equity Summit was an eye opening  and career influencing experience. Being a scholar and having the opportunity to contribute to the discussion on a novel and noble approach to health equity at a time when it’s needed. The meeting introduced us to other other investigators, administrators, journal editors, and society leaders broadened my perspective and opening the way for new opportunities and collaboration. This meeting has also connected ideas and work from basic science to implementation. It was inspiring to see so many passionate professionals working to advance equity and improve the future of health."

Interested in contributing to the future of evidence-based medicine? Become an Evidence Foundation Scholar and attend our upcoming virtual fall workshop (October 29-31, 2025) for free. Application close August 31, 2025. See evidencefoundation.org/scholarships.html for application details.

Learn more about Ali's project and other ways to get involved with GRADE at our upcoming free webinar, Monday, November 17th. Register to attend at this link.

USGN Congratulates Fall 2024 Scholar Michelle Hannum

The U.S. GRADE Network, in partnership with the Evidence Foundation, is proud to be able to offer scholarships for deserving applicants to attend our semi-annual GRADE Guideline Development Workshop with a waived registration fee. 

The scholarship allows workshop participants of all disciplines, fields, career stages, and backgrounds to learn about the GRADE framework for assessing certainty of evidence and formulating guideline recommendations. 

The fall 2024 scholarship recipient, Michelle Hannum, was chosen due to her proposed project on "The Promising Future of Evidence-Based Clinical Pathways in Reducing Healthcare Bias," undertaken as part of her work as a Guideline Development Project Manager at the Value Institute at the Medical University of South Carolina (MUSC) Health. The role of clinical pathways is to provide the right information (guideline recommendations) to the right people (electronic health record end-users) at the right time (based on patient data) in the right formats and using the right channels. Hannum presented data on pathway utilization at MUSC Health, which demonstrated that Heart Failure pathway utilization was approximately 16-18% and that utilization was equal across patient race/ethnicity and sex among this population. Furthermore, pathway utilization coincided with lower mortality rates, fewer 30-day readmissions and ICU days, and overall lower cost. 

When asked about her experience as a scholar, Hannum stated,

"The workshop does an outstanding job meeting individuals with where they are at in their GRADE journey, whether it be for career roles or personal goals. The information was presented in an engaging manner with plenty of opportunities for discussion and question-answering. The workshop provides an excellent foundation for understanding GRADE and its application."

Interested in being a scholar at the Spring 2025 GRADE Workshop in Washington, DC, May 7-9, 2025? Applications are due January 31. See details at www.evidencefoundation.org/scholarships/html.

EF Scholar Success Story: Nirjhar Ruth Ghosh

 New publication alert!

Nirjhar Ruth Ghosh, who attended the winter 2022 Systematic Review workshop as an Evidence Foundation scholar, recently published the results of her hard work in The Journal of Nutrition! The project, "Evidence-Based Practice Competencies Among Nutrition Professionals and Students: A Systematic Review" was originally presented by Ghosh to her fellow attendees of the virtual workshop. The results of the systematic review are now able to be read in detail at this link. 

In an accompanying editorial lauding the publication, Francene M. Steinberg wrote that "Ghosh et al. have provided a foundation for further consideration of steps to advance interprofessional competencies in EBP to optimize clinical nutrition decision making and patient care outcomes. Improved clarity about core competencies, innovative EBP curriculum and pedagogic approaches, and more rigorous research evaluations of EBP application and outcomes are all necessary components of the path forward."

Congratulations, Ruth!

Interested in being our next scholar success story? Applications for scholarships to attend our fully virtual GRADE Guideline Development Workshop are now open (deadline: August 31). Learn more at https://evidencefoundation.org/scholarships. 

=

Three's a Crowd: How to Deal with More than Two Arms in a Meta-Analysis

It is not uncommon to come across the following scenario: when conducting a meta-analysis between two arms (e.g., an active therapy vs. a placebo), the meta-analyst includes a study that actually included two active arms (e.g., two different doses of the same experimental drug vs. placebo, two different routes of administration, etc.) Let's say that both of these arms were relevant to the clinical question. How should meta-analysis be undertaken in this case? A new tutorial article published in Cochrane Evidence Synthesis and Methods gives a primer on how to approach this common conundrum. 

Including the study twice in the forest plot – for instance, with one dose versus placebo and the other versus the same placebo group – is statistically problematic. It leads to a "unit of analysis" error by essentially "double-counting" the participants in the control group and violating the assumption that every individual participant is only counted twice. (Aside: this is also a common error in meta-analyses combining multiple similar outcomes – e.g., including the handgrip strength of both the dominant and non-dominant hand in the same forest plot – and risks committing the same violation unless advanced multi-level statistical techniques are used to account for this). 

This leaves two basic options for including the data from more than two study arms into the same forest plot: combining interventions that are similar, and splitting the control group in half. For instance, if the three groups in question are as such (assuming a dichotomous outcome):

• Experimental group A: 50 participants, 45 of whom had the event.
• Experimental group B: 50 participants, 41 of whom had the event.
• Control group: 50 participants, 22 of whom had the event.

These two experimental groups can either be combined (100 participants, 89 of whom had the event) and compared to the control group as-is, or they can be split out and compared (on separate lines of the forest plot) to half of the control group on each line:

• Experimental group A (45 out of 50) versus control (11 out of 25)
• Experimental group B (41 out of 50) versus control (11 out of 25).

Both approaches will yield very similar pooled results.

In the case of a continuous outcome, the same general approaches can be applied. However, if pooling two or more arms together, a pooled mean and SD will need to be calculated using the following equations from the Cochrane Handbook:

Reference: Axon, E., Dwan, K., & Richardson, R. (2023) Multiarm studies and how to handle them in a meta-analysis: A tutorial. Cochrane Evidence Synthesis and Methods. Available at publisher's website here.