A Mendelian randomization study uses genetic variants as instrumental variables to assess the causal effect of LDL cholesterol on coronary heart disease. For an instrumental variable to be valid, which of the following assumptions must be satisfied?

• A The instrument is associated with the outcome independently of the exposure
• B The instrument affects the outcome only through the exposure (exclusion restriction) ✓
• C The instrument is correlated with known confounders
• D The sample size must exceed 10,000 subjects

Explanation

Three core assumptions are required for a valid instrumental variable: (1) relevance — the instrument (genetic variant) is strongly associated with the exposure (LDL); (2) independence — the instrument is not associated with confounders; (3) exclusion restriction — the instrument affects the outcome only through the exposure, not via any other pathway (pleiotropy violates this). Option A is incorrect because the instrument should affect the outcome ONLY through the exposure, not independently. Option C is opposite to what is required. Sample size is a power consideration, not a validity criterion.

Reference: Park's Textbook of Preventive and Social Medicine, 27th ed.

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