Methodological Issues in Systematic Review

- Formulating Questions -

Joseph Lau, MDTufts Medical Center EPC

AHRQ Annual Meeting September 10, 2008

Analytic framework for omega-3 FA intake and CVD

Clinical Outcomes

Intermediate Outcomes / Biological Effects

DeathMyocardial InfarctionStrokeUnstable Angina

Ventricular ArrhythmiaOthers

Tissue / Plasma LevelsRBC Phospholipid FAsWBC ghost Phosphlipid FAsOthers

Plasma Phospholipid FAsPlatelet Phospholipid FAs

AdverseEvents

Target PopulationsHealthy Adults Adults with elevated risk for CVD Adults with known CVD

Diabetes, Hypertension, Hyperlipidemia

Omega-3 Fatty Acid ConsumptionSource, Dosage, Duration

ModifiersDrug Interactions

Other

Blood PressureDiabetes MarkersHeart Rate Variability

CholesterolLipoprotein (a)C Reactive ProteinFibrinogen

Carotid Intima Media ThicknessCoronary Arteriography MarkersOthers

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

Participants Interventions Comparator Outcomes

Primary prevention

Fish, fish oil, ALA

Placebo Overall mortality

Secondary prevention

Dosage No control Sudden death

Background intake

Active comparator

Revascular-ization

Duration Stroke

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