John M Wentworth1,2,3, Naiara G Bediaga4,5, Lynne C Giles6, Mario Ehlers7,8, Stephen E Gitelman9, Susan Geyer10, Carmella Evans-Molina11, Leonard C Harrison4,5. 1. The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. wentworth@wehi.edu.au. 2. Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia. wentworth@wehi.edu.au. 3. Department of Diabetes and Endocrinology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia. wentworth@wehi.edu.au. 4. The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. 5. Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia. 6. School of Public Health, The University of Adelaide, Adelaide, SA, Australia. 7. Clinical Trials Group, Immune Tolerance Network, San Francisco, CA, USA. 8. Eli Lilly and Company, San Diego, CA, USA. 9. University of California at San Francisco, San Francisco, CA, USA. 10. University of South Florida, Tampa, FL, USA. 11. Indiana University School of Medicine, Indianapolis, IN, USA.
Abstract
AIMS/HYPOTHESIS: Beta cell function in type 1 diabetes is commonly assessed as the average plasma C-peptide concentration over 2 h following a mixed-meal test (CPAVE). Monitoring of disease progression and response to disease-modifying therapy would benefit from a simpler, more convenient and less costly measure. Therefore, we determined whether CPAVE could be reliably estimated from routine clinical variables. METHODS: Clinical and fasting biochemical data from eight randomised therapy trials involving participants with recently diagnosed type 1 diabetes were used to develop and validate linear models to estimate CPAVE and to test their accuracy in estimating loss of beta cell function and response to immune therapy. RESULTS: A model based on disease duration, BMI, insulin dose, HbA1c, fasting plasma C-peptide and fasting plasma glucose most accurately estimated loss of beta cell function (area under the receiver operating characteristic curve [AUROC] 0.89 [95% CI 0.87, 0.92]) and was superior to the commonly used insulin-dose-adjusted HbA1c (IDAA1c) measure (AUROC 0.72 [95% CI 0.68, 0.76]). Model-estimated CPAVE (CPEST) reliably identified treatment effects in randomised trials. CPEST, compared with CPAVE, required only a modest (up to 17%) increase in sample size for equivalent statistical power. CONCLUSIONS/ INTERPRETATION: CPEST, approximated from six variables at a single time point, accurately identifies loss of beta cell function in type 1 diabetes and is comparable to CPAVE for identifying treatment effects. CPEST could serve as a convenient and economical measure of beta cell function in the clinic and as a primary outcome measure in trials of disease-modifying therapy in type 1 diabetes.
AIMS/HYPOTHESIS: Beta cell function in type 1 diabetes is commonly assessed as the average plasma C-peptide concentration over 2 h following a mixed-meal test (CPAVE). Monitoring of disease progression and response to disease-modifying therapy would benefit from a simpler, more convenient and less costly measure. Therefore, we determined whether CPAVE could be reliably estimated from routine clinical variables. METHODS: Clinical and fasting biochemical data from eight randomised therapy trials involving participants with recently diagnosed type 1 diabetes were used to develop and validate linear models to estimate CPAVE and to test their accuracy in estimating loss of beta cell function and response to immune therapy. RESULTS: A model based on disease duration, BMI, insulin dose, HbA1c, fasting plasma C-peptide and fasting plasma glucose most accurately estimated loss of beta cell function (area under the receiver operating characteristic curve [AUROC] 0.89 [95% CI 0.87, 0.92]) and was superior to the commonly used insulin-dose-adjusted HbA1c (IDAA1c) measure (AUROC 0.72 [95% CI 0.68, 0.76]). Model-estimated CPAVE (CPEST) reliably identified treatment effects in randomised trials. CPEST, compared with CPAVE, required only a modest (up to 17%) increase in sample size for equivalent statistical power. CONCLUSIONS/ INTERPRETATION: CPEST, approximated from six variables at a single time point, accurately identifies loss of beta cell function in type 1 diabetes and is comparable to CPAVE for identifying treatment effects. CPEST could serve as a convenient and economical measure of beta cell function in the clinic and as a primary outcome measure in trials of disease-modifying therapy in type 1 diabetes.
Entities:
Keywords:
Adult; Beta cell function; Children; Clinical trial; Immune Tolerance Network; Immune therapy; Linear model; TrialNet; Type 1 diabetes
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