• Ari Voutilainen, Christina Brester, Mikko Kolehmainen, and Tomi-Pekka Tuomainen.
• Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
• Ann. Med. 2022 Dec 1; 54 (1): 1500-1510.

ObjectiveThe purpose of this study was to discover how considering multiplicative, additive, and interactive effects modifies results of a prospective cohort study on coronary heart disease (CHD) incidence and its main risk factors.Material And MethodsThe Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study provided the study material, 2682 Eastern Finnish middle-aged men, followed since the 1980s. We applied multiplicative and additive survival models together with different statistical metrics and confidence intervals for risk ratios and risk differences to estimate the nature of associations.ResultsThe mean (SD) follow-up time among men who were free of CHD at baseline (n = 1958) was 21.4 (10.4) years, and 717 (37%) of them had the disease and 301 (15%) died for CHD before the end of follow-up. All tested non-modifiable and modifiable risk factors statistically significantly predicted CHD incidence. We detected three interactions: circulating low-density lipoprotein cholesterol (LDL-C) × age, obesity × age, and obesity × smoking of which LDL-C × age was the most evident one. High LDL-C increased the risk of CHD more among men younger than 50 [risk ratio (RR) 2.10] than those older than 50 (RR 1.22). LDL-C status was the only additive covariate. The additive effect of high LDL-C increased almost linearly up to 18 years and then reached a plateau. The simple multiplicative survival model stressed glycemic status as the strongest modifiable risk factor for developing CHD [hazard ratio (HR) for diabetes vs. normoglycemia was 2.69], whereas the model considering interactions and time dependence emphasised the role of LDL-C status (HR for high LDL-C vs. lower than borderline was 4.43). Age was the strongest non-modifiable predictor.ConclusionsIncluding covariate interactions and time dependence in survival models potentially refine results of epidemiological analyses and ease to define the order of importance across CHD risk factors. KEY MESSAGESIncluding covariate interactions and time dependence in survival models potentially refine results of epidemiological analyses on coronary heart disease.Including covariate interactions and time dependence in survival models potentially ease to define the order of importance across coronary heart disease risk factors.

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