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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 weighted Schoenfeld residual plots are displayed for non-Hispanic white ethnicity (NHW) (a) and a 5-year difference in maternal age (b) in the prospective DAISY cohort. The x-axis represents age in years and the y-axis represents the coefficient estimate for non-Hispanic white ethnicity in (a) and coefficient for maternal age in (b). The dots represent the residuals for each individual. The solid line is a smoothing-spline fit to the plot, with the dashed lines representing the 95% confidence interval. The global PH test P values based on the Schoenfeld residuals are 0.02 and 0.01 for NHW ethnicity and a 5-year difference in maternal age, respectively, indicating a violation of the PH assumption.
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fig2: The weighted Schoenfeld residual plots are displayed for non-Hispanic white ethnicity (NHW) (a) and a 5-year difference in maternal age (b) in the prospective DAISY cohort. The x-axis represents age in years and the y-axis represents the coefficient estimate for non-Hispanic white ethnicity in (a) and coefficient for maternal age in (b). The dots represent the residuals for each individual. The solid line is a smoothing-spline fit to the plot, with the dashed lines representing the 95% confidence interval. The global PH test P values based on the Schoenfeld residuals are 0.02 and 0.01 for NHW ethnicity and a 5-year difference in maternal age, respectively, indicating a violation of the PH assumption.

Mentions: We first assessed age-related heterogeneity of two fixed covariates: NHW ethnicity and maternal age at birth. The supremum test P value was 0.01 for NHW ethnicity adjusting for HLA-DR3/4, DQB1*0302 genotype and first-degree relative status, indicating a violation of PH (Table 3). The weighted Schoenfeld residuals had a global PH test P = 0.02 and an individual PH test P = 0.01, indicating a violation of PH (Figure 2(a)). We modeled the RCS to evaluate the HR as a function of time. NHW ethnicity showed an overall significant association with IA risk adjusting for HLA-DR3/4, DQB1*0302 genotype and first-degree relative status (Association P = 0.03) (Table 3). Based on rejection of the hypothesis, the nonconstant association was tested, producing a P = 0.01, indicating non-PH (Table 3). Finally, a nonlinear association was tested based on rejection of the hypothesis for the nonconstant association, which was not significant (Nonlinear P = 0.62), indicating a linear decrease in IA risk associated with NHW ethnicity over time (Table 3). The restricted cubic spline demonstrated an elevated risk in early childhood (age 2 HR: 1.74, 95% CI: 0.90, 3.36) diminishing with increasing age (age 11 HR: 0.64, 95% CI: 0.38, 1.06) (Figure 3(a)).


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 weighted Schoenfeld residual plots are displayed for non-Hispanic white ethnicity (NHW) (a) and a 5-year difference in maternal age (b) in the prospective DAISY cohort. The x-axis represents age in years and the y-axis represents the coefficient estimate for non-Hispanic white ethnicity in (a) and coefficient for maternal age in (b). The dots represent the residuals for each individual. The solid line is a smoothing-spline fit to the plot, with the dashed lines representing the 95% confidence interval. The global PH test P values based on the Schoenfeld residuals are 0.02 and 0.01 for NHW ethnicity and a 5-year difference in maternal age, respectively, indicating a violation of the PH assumption.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: The weighted Schoenfeld residual plots are displayed for non-Hispanic white ethnicity (NHW) (a) and a 5-year difference in maternal age (b) in the prospective DAISY cohort. The x-axis represents age in years and the y-axis represents the coefficient estimate for non-Hispanic white ethnicity in (a) and coefficient for maternal age in (b). The dots represent the residuals for each individual. The solid line is a smoothing-spline fit to the plot, with the dashed lines representing the 95% confidence interval. The global PH test P values based on the Schoenfeld residuals are 0.02 and 0.01 for NHW ethnicity and a 5-year difference in maternal age, respectively, indicating a violation of the PH assumption.
Mentions: We first assessed age-related heterogeneity of two fixed covariates: NHW ethnicity and maternal age at birth. The supremum test P value was 0.01 for NHW ethnicity adjusting for HLA-DR3/4, DQB1*0302 genotype and first-degree relative status, indicating a violation of PH (Table 3). The weighted Schoenfeld residuals had a global PH test P = 0.02 and an individual PH test P = 0.01, indicating a violation of PH (Figure 2(a)). We modeled the RCS to evaluate the HR as a function of time. NHW ethnicity showed an overall significant association with IA risk adjusting for HLA-DR3/4, DQB1*0302 genotype and first-degree relative status (Association P = 0.03) (Table 3). Based on rejection of the hypothesis, the nonconstant association was tested, producing a P = 0.01, indicating non-PH (Table 3). Finally, a nonlinear association was tested based on rejection of the hypothesis for the nonconstant association, which was not significant (Nonlinear P = 0.62), indicating a linear decrease in IA risk associated with NHW ethnicity over time (Table 3). The restricted cubic spline demonstrated an elevated risk in early childhood (age 2 HR: 1.74, 95% CI: 0.90, 3.36) diminishing with increasing age (age 11 HR: 0.64, 95% CI: 0.38, 1.06) (Figure 3(a)).

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