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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

Soyfood and isoflavone intake and risk of type 2 diabetes in Vietnamese adults.

BACKGROUND/OBJECTIVES: Animal studies have demonstrated that soy isoflavones exert antidiabetic effects. However, evidence regarding the association between soyfood intake, a unique source of isoflavones, and type 2 diabetes remains inconclusive. This study assessed the relationship between habitual intakes of soyfoods and major isoflavones and risk of type 2 diabetes in Vietnamese adults. SUBJECTS/METHODS: A hospital-based case-control study was conducted in Vietnam during 2013-2015. A total of 599 newly diagnosed diabetic cases (age 40-65 years) and 599 hospital-based controls, frequency matched by age and sex, were recruited in Hanoi, capital city of Vietnam. Information on frequency and quantity of soyfood and isoflavone intake, together with demographics, habitual diet and lifestyle characteristics, was obtained from direct interviews using a validated and reliable questionnaire. Unconditional logistic regression analyses were performed to examine the association between soy variables and type 2 diabetes risk. RESULTS: Higher intake of total soyfoods was significantly associated with a lower risk of type 2 diabetes; the adjusted odds ratio (OR) for the highest versus the lowest intake was 0.31 (95% confidence interval (CI): 0.21-0.46; P<0.001). An inverse dose-response relationship of similar magnitude was also observed for total isoflavone intake (OR: 0.35; 95% CI: 0.24 to 0.49; P<0.001). In addition, inverse associations of specific soyfoods (soy milk, tofu and mung bean sprout) and major isoflavones (daidzein, genistein and glycitein) with the type 2 diabetes risk were evident. CONCLUSIONS: Soyfood and isoflavone intake was associated with a lower type 2 diabetes risk in Vietnamese adults.European Journal of Clinical Nutrition advance online publication, 10 May 2017; doi:10.1038/ejcn.2017.76