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Additive and Multiplicative Interactions Between Genetic Risk Score and Family History and Lifestyle in Relation to Risk of Type 2 Diabetes.

ABSTRACT: We examined interactions between lifestyle factors and genetic risk of type 2 diabetes (T2D-GR), captured by genetic risk score (GRS) and family history (FH). Our initial study cohort included 20,524 European-ancestry participants, of whom 1,897 developed incident T2D, in the Nurses' Health Study (1984-2016), Nurses' Health Study II (1989-2016), and Health Professionals Follow-up Study (1986-2016). The analyses were replicated in 19,183 European-ancestry controls and 2,850 incident T2D cases in the Women's Genome Health Study (1992-2016). We defined 2 categories of T2D-GR: high GRS (upper one-third) with FH and low GRS or without FH. Compared with participants with the healthiest lifestyle and low T2D-GR, the relative risk of T2D for participants with the healthiest lifestyle and high T2D-GR was 2.24 (95% confidence interval (CI): 1.76, 2.86); for participants with the least healthy lifestyle and low T2D-GR, it was 4.05 (95% CI: 3.56, 4.62); and for participants with the least healthy lifestyle and high T2D-GR, it was 8.72 (95% CI: 7.46, 10.19). We found a significant departure from an additive risk difference model in both the initial and replication cohorts, suggesting that adherence to a healthy lifestyle could lead to greater absolute risk reduction among those with high T2D-GR. The public health implication is that a healthy lifestyle is important for diabetes prevention, especially for individuals with high GRS and FH of T2D.

SUBMITTER: Ding M

PROVIDER: S-EPMC7462250 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Additive and multiplicative regression models of habituation were compared regarding the fit to looking times from a habituation experiment with infants aged between 3 and 11 months. In contrast to earlier studies, the current study considered multiple probability distributions, namely Weibull, gamma, lognormal and normal distribution. In the habituation experiment the type of contrast between the habituation and the test trial was varied (luminance, color or orientation contrast), crossed with the number of habituation trials (1, 3, 5, or 7 habituation trials) and crossed with three age cohorts (4, 7, 10 months). The initial mean LT to dark stimuli (around 3.7 s) was considerably shorter than the mean LT to green and gray stimuli (around 5 s). Infants showed the strongest dishabituation to changes from dark to bright (luminance contrast) and weak-to-no dishabituation to a 90-degrees rotation of the gray stimuli (orientation contrast). The dishabituation was stronger after five and seven habituation trials, but the result was not statistically robust. The gamma distribution showed the best fit in terms of log-likelihood and mean absolute error and the best predictive performance. Furthermore, the gamma distribution showed small correlations between parameters relative to other models. The normal additive model showed an inferior fit and medium correlations between the parameters. In particular, the positive correlation between the initial looking time (LT) and the habituation rate was likely responsible for a different interpretation relative to the multiplicative models of the main effect of age on the habituation rate. Otherwise, the additive and multiplicative models provided similar statistical conclusions. The performance of the model versions without pooling and with partial pooling across participants (also called random-effects, multi-level or hierarchical models) were compared. The latter type of models showed worse data fit but more precise predictions and reduced correlations between the parameters. The performance of model variants with auto-regressive time structures were explored but showed considerably worse fit. The performance of quadratic models that allowed non-monotonic changes in LTs were investigated as well. However, when fitted with LT data, these models did not produce non-monotonic change in LTs. The study underscores the utility of partial-pooling models in terms of providing more accurate predictions. Further, it agrees with previous research in that a multiplicative LT model is preferable. Nevertheless, the current results suggest that the impact of the choice of an additive model on the statistical inference is less dramatic then previously assumed.

Project description:Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association.A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created.A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history.Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.

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Additive and Multiplicative Interactions Between Genetic Risk Score and Family History and Lifestyle in Relation to Risk of Type 2 Diabetes.

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