Skip to main content

Table 5 Summary of recommendations for investigating clinical heterogeneity in systematic reviews

From: Investigating clinical heterogeneity in systematic reviews: a methodologic review of guidance in the literature

Recommendation Category Recommendation Description
A-priori planning 1. All plans for investigating clinical heterogeneity should be made explicit, a-priori (e.g., in the protocol for the systematic review).
Clinical expertise 2. The review/investigative team should include clinical experts or state a plan for consulting clinical experts during the review protocol development and implementation (e.g., when choosing clinical covariates and when interpreting the findings).
Covariate rationale 3. Clinical covariates should be chosen that have a clearly stated rationale for their importance (e.g., a pathophysiological argument, reference to the results of a previous trial).
Thinking through covariate categories 4. Review teams should think through the following categories to determine if related covariates might logically influence the treatment effect in their particular review: participant level, intervention level, outcome level, research setting, or others unique to their research question.
Covariate hierarchy 5. A logical hierarchy of clinical covariates should be formed and investigated only if there is sufficient rationale and a sufficient number of trials available (10 trials per covariate).
Post hoc covariate identification 6. State any plans to include additional covariates after looking at the data (post hoc) from included studies (e.g., forest plots, radial plots) and how they plan to do this.
Statistical methods 7. Describe a-priori the statistical methods proposed to investigate identified covariates. Refer to accepted texts or published papers in the area to be sure to implement these methods in a valid manner. Include an individual with experience in conducting these analyses.1
Data sources 8. Aggregate patient data: Reasonable for investigating trial level covariates
9. Individual patient data: Consider when investigating participant level covariates (otherwise results are subject to ecologic bias)
Interpretation 10. A. Protocol: Describe how the results of any findings are going to be interpreted and used in the overall synthesis of evidence. B. Review: Consider the observational nature of these investigations; consider confounds and important potential biases; consider magnitude of the effect, confidence intervals and directionality of the effect.
  1. 1 We do not provide detailed recommendations for statistical analyses here because of the breath and complexity of this topic. Instead we suggest that one refer to accepted resources and well-trained individuals with expertise in the area.