Table 1.

Specification and emulation of a target trial of statin therapy and colorectal cancer risk using observational data from linked electronic health records accessed through the CALIBER resource

		Target trial emulation
Protocol	Target trial specification	Cohort analysis	Case-control analysis
Eligibility criteria	Aged ≥30 years between January 1998 and February 2016 No history of cancer (except nonmelanoma skin cancer) No statin contraindication (hepatic impairment or myopathy) No statin prescription within the past year LDL cholesterol <5 mmol/L At least 1 year of up-to-standard data in a CPRD practice At least 1 year of potential follow-up Baseline is defined as the first month in which all eligibility criteria are met	Same as for the target trial   We defined hepatic impairment as a code for hepatic failure or ALT ≥120 IU/L and myopathy as codes for its symptoms: muscle aches, pain or weakness   We required information on laboratory values measured during the past year and lifestyle factors during the past 4 years	Same as for the cohort analysis   We performed incidence density sampling of the eligible individuals, selecting 1000 controls per 1 colorectal cancer case
Treatment strategies	(i) Initiation of any statin therapy at baseline and continuation over follow-up until the development of a contraindication (hepatic impairment or myopathy)   (ii) No initiation of statin therapy over follow-up until the development of an indication (LDL cholesterol ≥5 mmol/L)   Treatment is considered continuous if there is a gap of <30 days between successive prescriptions. When clinically warranted during the follow-up, patients and their physicians will decide whether to start stop or switch therapy. Participants must have a primary care consultation at least once every 4 years to assess prognostic factors associated with adherence and loss to follow-up	Same as for the target trial   We defined the date of medication initiation to be the first date of a prescription   We calculated discontinuation dates using the daily dose and quantity of pills in the prescription	Same as for the cohort analysis
Treatment assignment	Individuals are randomly assigned to a strategy at baseline, and individuals and their treating physicians will be aware of the assigned treatment strategy	We classified individuals according to the strategy that their data were compatible with at baseline and attempted to emulate randomization by adjusting for baseline confounders	Same as for the cohort analysis
Outcomes	Colorectal cancer	Same as for the target trial   Colorectal cancer diagnoses were recorded as Read codes and ICD-10 codes	Same as for the cohort analysis
Follow-up	Starts at baseline and ends at the month of colorectal cancer diagnosis, death, loss to follow-up (transfer out of the practice or incomplete follow-up [4 years after the last recorded prognostic factors]), 6 years after baseline or administrative end of follow-up (end of practice data collection or February 2016), whichever happens first	Same as for the target trial	Same as for the cohort analysis
Causal contrasts	Intention-to-treat effect and per-protocol effect	Observational analogue of intention-to-treat and per-protocol effect	Same as for the cohort analysis
Statistical analysis	Intention-to-treat analysis: apply inverse-probability weights to adjust for pre- and post-baseline prognostic factors associated with loss to follow-up   Per-protocol analysis: censor individuals if and when they deviate from their assigned treatment strategy and apply inverse-probability weights to adjust for pre- and post-baseline prognostic factors associated with adherence and loss to follow-up14	Same as for the target trial with adjustment for baseline confounders	Same as for the cohort analysis

ALT, alanine transaminase; CPRD, Clinical Practice Research Database; LDL, low-density lipoprotein.