TABLE 2.

Emulation of a target trial of dietary interventions using observational data from the Health Professionals Follow-up Study, Nurses’ Health Study, and Nurses’ Health Study II

	Target trial specification	Target trial emulation
Eligibility criteria	Age ≥25 y, no history of diabetes, cardiovascular disease, and cancer.	Same. We also required complete questions on diet and covariates and report plausible energy intake (800 to 4200 kcal/d in men; 500 to 3500 kcal/d in women) at prebaseline and baseline questionnaires.
		• Baseline is defined as the date of return of the second dietary questionnaire (1990 for HPFS, 1986 for NHS, and 1995 for NHS II) to allow for adjustment for prebaseline diet.
Dietary strategies	Each individual would be assigned to 1 of 14 following strategies:• No intervention (usual diet)• Joint intervention on all 6 food-based components of the AHA 2020 Dietary Goals• Intervention on only 1 of the components (6 separate strategies)• Joint intervention on 5 of the 6 components (6 strategies, leaving 1 component out under each strategy)	Same. We assumed that each 4-y dietary questionnaire accurately reflects 1) the average diet during the previous 4-y period; and 2) the intended diet (under no intervention) that the individual would have reported at the start of the 4-y period.
	Each strategy is followed for 20 y.
	Fish interventions apply to nonvegetarians only.
	Participants assigned to a dietary strategy are expected to maintain their dietary intake within the range prespecified by the corresponding intervention.
Assignment	Individuals are randomly assigned to a dietary strategy.	We attempted to emulate randomized assignment by adjusting for prebaseline or baseline covariates: baseline age at enrollment; family history of myocardial infarction before 60 y; smoking index; aspirin use; menopausal status (NHS/NHS II); menopausal hormone therapy (NHS/NHS II); baseline diagnosis of hypertension or hypercholesterolemia; and prebaseline values of fruits and vegetables, whole grains, processed meat, fish, sugar- sweetened beverages, legumes/nuts/seeds, and alcohol; and total energy intake.
Outcome	Primary outcome: 20-y risk of all-cause mortality.	Same.
	Secondary outcomes: 20-y risk of death from CVD, cancer, and other causes.
Follow-up	Starts at baseline and ends at death, incomplete follow-up, or 20 y after baseline, whichever occurs first.	Same. Incomplete follow-up is defined as questionnaire nonresponse or incomplete responses to dietary questions.
Causal contrast	Intention-to-treatment effect.	Observational analog of per-protocol effect.
	Per-protocol effect.
Statistical analysis	Intention-to-treat analysis.	Same as per-protocol analysis.
	Per-protocol analysis: Apply g-formula to compare 20-y risk of death between groups receiving each treatment strategy with adjustment for pre- and postbaseline prognostic factors associated with adherence to strategies and loss to follow-up.

Abbreviations: AHA, American Heart Association; CVD, cardiovascular disease; HPFS, Health Professionals Follow-Up Study; NHS, Nurses’ Health Study; NHS II, Nurses’ Health Study II.