A comparison of methods to adjust for continuous covariates in the analysis of randomised trials.


Kahan, BC; Rushton, H; Morris, TP; Daniel, RM; (2016) A comparison of methods to adjust for continuous covariates in the analysis of randomised trials. BMC Med Res Methodol, 16 (1). p. 42. ISSN 1471-2288 DOI: 10.1186/s12874-016-0141-3

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Abstract

Although covariate adjustment in the analysis of randomised trials can be beneficial, adjustment for continuous covariates is complicated by the fact that the association between covariate and outcome must be specified. Misspecification of this association can lead to reduced power, and potentially incorrect conclusions regarding treatment efficacy. We compared several methods of adjustment to determine which is best when the association between covariate and outcome is unknown. We assessed (a) dichotomisation or categorisation; (b) assuming a linear association with outcome; (c) using fractional polynomials with one (FP1) or two (FP2) polynomial terms; and (d) using restricted cubic splines with 3 or 5 knots. We evaluated each method using simulation and through a re-analysis of trial datasets. Methods which kept covariates as continuous typically had higher power than methods which used categorisation. Dichotomisation, categorisation, and assuming a linear association all led to large reductions in power when the true association was non-linear. FP2 models and restricted cubic splines with 3 or 5 knots performed best overall. For the analysis of randomised trials we recommend (1) adjusting for continuous covariates even if their association with outcome is unknown; (2) keeping covariates as continuous; and (3) using fractional polynomials with two polynomial terms or restricted cubic splines with 3 to 5 knots when a linear association is in doubt.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Medical Statistics
Research Centre: Centre for Statistical Methodology
PubMed ID: 27068456
Web of Science ID: 373758800001
URI: http://researchonline.lshtm.ac.uk/id/eprint/2537244

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