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Assessing age-related etiologic heterogeneity in the onset of islet autoimmunity.

Frederiksen BN, Kroehl M, Barón A, Lamb MM, Crume TL, Sontag MK, Rewers M, Norris JM - Biomed Res Int (2015)

Bottom Line: Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected.A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk.Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, 13001 E. 17th Place, Box B119, Aurora, CO 80045, USA.

ABSTRACT
Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW) ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA) levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.

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The restricted cubic spline function for erythrocyte membrane n-3 fatty acid levels and islet autoimmunity development in the prospective DAISY cohort displays a linear decrease in risk across childhood. The x-axis represents age in years and the y-axis represents the hazard ratio on the log scale. The solid line represents the hazard ratio and the dashed lines represent the pointwise 95% confidence bands.
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fig4: The restricted cubic spline function for erythrocyte membrane n-3 fatty acid levels and islet autoimmunity development in the prospective DAISY cohort displays a linear decrease in risk across childhood. The x-axis represents age in years and the y-axis represents the hazard ratio on the log scale. The solid line represents the hazard ratio and the dashed lines represent the pointwise 95% confidence bands.

Mentions: We then assessed age-related heterogeneity for the time-varying covariate, erythrocyte membrane n-3 FA levels, by fitting a restricted cubic spline model (Figure 4). Erythrocyte membrane n-3 FA levels had an overall significant association with IA risk (Association P = 0.001) adjusting for HLA-DR3/4, DQB1*0302 genotype and first-degree relative status, previously established in DAISY by Norris et al. [21]. With rejection of this hypothesis, the nonconstant association of erythrocyte membrane n-3 FA levels was tested and resulted in a P = 0.001, indicating non-PH (Figure 4). Finally, a nonlinear association was tested based on rejection of the hypothesis for the nonconstant association, which was not significant (P = 0.17), indicating a linear decrease in IA risk associated with erythrocyte membrane n-3 FA levels over time (age 2 HR: 1.08, 95% CI: 0.75, 1.56 and age 11 HR: 0.30, 95% CI: 0.14, 0.64) (Table 3 and Figure 4).


Assessing age-related etiologic heterogeneity in the onset of islet autoimmunity.

Frederiksen BN, Kroehl M, Barón A, Lamb MM, Crume TL, Sontag MK, Rewers M, Norris JM - Biomed Res Int (2015)

The restricted cubic spline function for erythrocyte membrane n-3 fatty acid levels and islet autoimmunity development in the prospective DAISY cohort displays a linear decrease in risk across childhood. The x-axis represents age in years and the y-axis represents the hazard ratio on the log scale. The solid line represents the hazard ratio and the dashed lines represent the pointwise 95% confidence bands.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389824&req=5

fig4: The restricted cubic spline function for erythrocyte membrane n-3 fatty acid levels and islet autoimmunity development in the prospective DAISY cohort displays a linear decrease in risk across childhood. The x-axis represents age in years and the y-axis represents the hazard ratio on the log scale. The solid line represents the hazard ratio and the dashed lines represent the pointwise 95% confidence bands.
Mentions: We then assessed age-related heterogeneity for the time-varying covariate, erythrocyte membrane n-3 FA levels, by fitting a restricted cubic spline model (Figure 4). Erythrocyte membrane n-3 FA levels had an overall significant association with IA risk (Association P = 0.001) adjusting for HLA-DR3/4, DQB1*0302 genotype and first-degree relative status, previously established in DAISY by Norris et al. [21]. With rejection of this hypothesis, the nonconstant association of erythrocyte membrane n-3 FA levels was tested and resulted in a P = 0.001, indicating non-PH (Figure 4). Finally, a nonlinear association was tested based on rejection of the hypothesis for the nonconstant association, which was not significant (P = 0.17), indicating a linear decrease in IA risk associated with erythrocyte membrane n-3 FA levels over time (age 2 HR: 1.08, 95% CI: 0.75, 1.56 and age 11 HR: 0.30, 95% CI: 0.14, 0.64) (Table 3 and Figure 4).

Bottom Line: Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected.A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk.Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, 13001 E. 17th Place, Box B119, Aurora, CO 80045, USA.

ABSTRACT
Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW) ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA) levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.

Show MeSH
Related in: MedlinePlus