Methodological Issues in Systematic Review - Formulating Questions - Joseph Lau, MD Tufts Medical Center EPC AHRQ Annual Meeting September 10, 2008

Analytic framework for omega-3 FA intake and CVD

Specific Key Questions 1.What is the efficacy or association of omega-3 fatty acids (DHA, EPA or ALA supplements, and fish consumption) in reducing CVD events (including all-cause mortality, CVD mortality, non-fatal CVD events, and new diagnosis of CVD)? In patients without known CVD (primary prevention) and with known CVD (secondary prevention).

Specific Key Questions 2. Relative effects of omega-3 fatty acid sources, with specific emphasis on compositions, dosages, the ratio of omega- 6 to omega-3 fatty acids, and potential interactions due to duration of intervention or exposure. What adverse events related to omega-3 fatty acid dietary supplements are reported in studies?

Participants Primary Prevention - patients without prior history of cardiovascular disease –Country –Background diet Secondary Prevention – patients with prior history of cardiovascular disease

Interventions Fish –Different kinds, preparation, amount, how intake was estimated Fish oil supplements –Eicosapentaenoic acid (EPA) / Docosahexaenoic acid (DHA) α-linolenic acid [ALA] (walnut, canola oil, flax seed, etc.)

Outcomes (endpoints) Clinical outcomes (events) –Overall mortality –Stroke –Myocardial infarction –Sudden death –revascularization Surrogate/intermediate outcomes (biomarkers, measurements) –Blood pressure –Lipid levels

The PICO method to formulate research question on interventions ParticipantsInterventionsComparatorOutcomes Primary prevention Fish, fish oil, ALA PlaceboOverall mortality Secondary prevention DosageNo controlSudden death Background intake Active comparator Revascular- ization DurationStroke Blood pressure

Study design RCT Cohort Case-control Cross-sectional Other criteria –Study size –Year, language, etc

Additional inclusion criteria Published English language literature Experimental or observational studies Reported original CVD outcome data and evaluated any potential source of omega-3 fatty acids At least 5 human subjects At least 1-year duration

Issues in formulating a question Narrow versus broad (for individual or population) Clinically meaningful and useful (based on sound biological and epidemiological principles) Very broadly defined questions may be criticized for mixing apples and oranges Very narrowly focused questions may have no data or have limited generalizability and sometimes may lead to misinterpretations