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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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Flow chart illustrating the formation of the cohorts for the investigation of age-related heterogeneity.
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fig1: Flow chart illustrating the formation of the cohorts for the investigation of age-related heterogeneity.

Mentions: The DAISY cohort is composed of 2,547 children, of whom 188 have developed IA. Nineteen IA cases were positive for autoantibodies on their first clinic visits; these left-censored cases were removed from the analysis. We examined NHW ethnicity and maternal age at birth as fixed covariates for age-related heterogeneity in this cohort. We also assessed the time-varying covariate, erythrocyte membrane n-3 FA levels, for age-related heterogeneity. As described previously [22], erythrocyte membrane n-3 FA levels were investigated in a case-cohort design, for which a representative sample of 380 children (i.e. subcohort) was selected from the main DAISY cohort using stratified sampling based on HLA-DR genotype and family history of T1D; 313 of these children had erythrocyte n-3 FA measurements. Erythrocyte n-3 FA levels were measured at 9, 15, and 24 months of age and annually thereafter. The median age at which n-3 FA levels were determined was 6.9 years (IQR: 5.2 years). During follow-up, 14 children with erythrocyte membrane n-3 FA levels developed IA within the subcohort. We supplemented these with 46 children who developed IA outside of the subcohort to complete our case-cohort study population. Therefore, 60 children with IA and 299 IA negative children were included in the analysis of erythrocyte membrane n-3 FA levels (see Figure 1 for flow-chart illustrating the formation of the analysis cohorts).


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)

Flow chart illustrating the formation of the cohorts for the investigation of age-related heterogeneity.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Flow chart illustrating the formation of the cohorts for the investigation of age-related heterogeneity.
Mentions: The DAISY cohort is composed of 2,547 children, of whom 188 have developed IA. Nineteen IA cases were positive for autoantibodies on their first clinic visits; these left-censored cases were removed from the analysis. We examined NHW ethnicity and maternal age at birth as fixed covariates for age-related heterogeneity in this cohort. We also assessed the time-varying covariate, erythrocyte membrane n-3 FA levels, for age-related heterogeneity. As described previously [22], erythrocyte membrane n-3 FA levels were investigated in a case-cohort design, for which a representative sample of 380 children (i.e. subcohort) was selected from the main DAISY cohort using stratified sampling based on HLA-DR genotype and family history of T1D; 313 of these children had erythrocyte n-3 FA measurements. Erythrocyte n-3 FA levels were measured at 9, 15, and 24 months of age and annually thereafter. The median age at which n-3 FA levels were determined was 6.9 years (IQR: 5.2 years). During follow-up, 14 children with erythrocyte membrane n-3 FA levels developed IA within the subcohort. We supplemented these with 46 children who developed IA outside of the subcohort to complete our case-cohort study population. Therefore, 60 children with IA and 299 IA negative children were included in the analysis of erythrocyte membrane n-3 FA levels (see Figure 1 for flow-chart illustrating the formation of the analysis cohorts).

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