Table 1.

Issues and Corresponding Recommendations for Systematic Reviews Aiming to Inform Guidelines in Patients with Comorbidity

Systematic review step [Description]	Issues of particular importance to systematic reviews of multimorbidity	Specific recommendations
A. Prepare the topic
This includes:   a. Refining key questions with stakeholder engagement   b. Developing an analytic framework   c. Assessing feasibility and creating time lines	When the CPG workgroup and the systematic review team do not overlap, there is risk of miscommunication of: • The focus and scope of the CPGs. • The strengths and limitations of systematic reviews that are based on literature data. • The cost and effort involved in performing a systematic review. Systematic reviews of multimorbidity will have to address the presence and magnitude of interactions between conditions and treatments. To become manageable, they may have to be organized into several key questions. The logic and assumptions behind the key questions should be transparent.	1. Establish early communication between the CPG workgroup and the systematic review team to refine scope and goals for the systematic review, and educate CPG workgroup members who lack Evidence-Based Medicine (EBM) expertise. 2. Decide on the feasibility of performing an informative systematic review within time line and resource constraints.
B. Establish a protocol
This includes defining the:
a. Population of interest	Most studies will not enroll exactly the population that is the focus of the CPG. One has to operationalize which studies are applicable enough to the CPG. For, example, is it necessary that all patients enrolled in a study have all conditions of interest? If not, how prevalent should the each condition be to make a study eligible for inclusion?	3. Engage the CPG workgroup to define: a. The conditions that are most likely to lead to heterogeneity of treatment effect b. Population eligibility criteria that are as inclusive as meaningful
b. Comparison of interest (intervention, comparator)	Multimorbid patients are likely to receive many treatments in addition to the intervention and comparator of interest. For example, if the comparison of interest is A vs. B, the background treatments in two studies may be X 1 and X 2. Combining studies comparing A + X 1 vs. B + X 1 with studies comparing A + X 2 vs. B + X 2 is not meaningful if the background treatment interacts with the interventions (A, B) or populations of interest.	4. Engage the CPG clinical experts to help evaluate the likelihood for interaction between any background interventions and the examined intervention or comparator.
c. Outcome of interest	The relative importance of outcomes may differ for patients with multimorbidity compared to patients with a single condition. Outcomes can be classified in order of importance to patients into: • Critical (e.g., mortality, disabling stroke), • Important clinical, often representing competing risks (e.g., myocardial infarction) • Intermediate clinical (e.g., hypertension), and • Minor/other (e.g., anemia).	5. Engage the CPG workgroup to identify critical or important clinical outcomes.
d. Study designs of interest	We anticipate scarcity of data on interactions between the comorbidities and interventions of interest. Using a best-available-evidence approach, we would consider both randomized and nonrandomized studies.	6. Consider including well-designed, well-conducted and well-analyzed nonrandomized comparative data.
C. Identify studies
	[Same considerations as in all systematic reviews]	[Follow standard systematic review guidance]
D. Extract data
	[Same considerations as in all systematic reviews]	[Follow standard systematic review guidance]
E. Assess the risk of bias
	Treatment-by-comorbidity interactions analyses are not commonly reported in primary studies. It is possible that the reporting of interaction analyses is dependent on the findings (analysis reporting bias).	7. Assess the likelihood of selective reporting biases (including publication bias).
F. Synthesize information
	As above, treatment-by-comorbidity interactions may be incompletely and selectively reported, limiting ability for quantitative analyses. Further, there is lack of statistical methods for the joint meta-analysis of main and interaction effects accounting for their covariance.	8. Perform a nonquantitative synthesis of the available information. 9. If applicable, perform quantitative analysis of the main treatment effects and treatment-by-comorbidity interaction effects using methods that allow for between-study heterogeneity.
G. Evaluate the strength of the evidence base
	Follow a systematic approach to assess the strength of the body of evidence with respect to each outcome of interest.	10. Assess the strength of the evidence for each outcome of interest.
H. Report findings
	[Same considerations as in all systematic reviews]	[Follow standard systematic review guidance]