RESUMEN
Clinical trials seeking type 1 diabetes prevention are challenging in terms of identifying patient populations likely to progress to type 1 diabetes within limited (i.e., short-term) trial durations. Hence, we sought to improve such efforts by developing a quantitative disease progression model for type 1 diabetes. Individual-level data obtained from the TrialNet Pathway to Prevention and The Environmental Determinants of Diabetes in the Young natural history studies were used to develop a joint model that links the longitudinal glycemic measure to the timing of type 1 diabetes diagnosis. Baseline covariates were assessed using a stepwise covariate modeling approach. Our study focused on individuals at risk of developing type 1 diabetes with the presence of two or more diabetes-related autoantibodies (AAbs). The developed model successfully quantified how patient features measured at baseline, including HbA1c and the presence of different AAbs, alter the timing of type 1 diabetes diagnosis with reasonable accuracy and precision (<30% RSE). In addition, selected covariates were statistically significant (p < 0.0001 Wald test). The Weibull model best captured the timing to type 1 diabetes diagnosis. The 2-h oral glucose tolerance values assessed at each visit were included as a time-varying biomarker, which was best quantified using the sigmoid maximum effect function. This model provides a framework to quantitatively predict and simulate the time to type 1 diabetes diagnosis in individuals at risk of developing the disease and thus, aligns with the needs of pharmaceutical companies and scientists seeking to advance therapies aimed at interdicting the disease process.
Asunto(s)
Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/prevención & control , Prueba de Tolerancia a la Glucosa , Autoanticuerpos , Progresión de la Enfermedad , Glucemia/metabolismoRESUMEN
The development of therapies to prevent or delay the onset of type 1 diabetes (T1D) remains challenging, and there is a lack of qualified biomarkers to identify individuals at risk of developing T1D or to quantify the time-varying risk of conversion to a diagnosis of T1D. To address this drug development need, the T1D Consortium (i) acquired, remapped, integrated, and curated existing patient-level data from relevant observational studies, and (ii) used a model-based approach to evaluate the utility of islet autoantibodies (AAs) against insulin/proinsulin autoantibody, GAD65, IA-2, and ZnT8 as biomarkers to enrich subjects for T1D prevention. The aggregated dataset was used to construct an accelerated failure time model for predicting T1D diagnosis. The model quantifies presence of islet AA permutations as statistically significant predictors of the time-varying probability of conversion to a diagnosis of T1D. Additional sources of variability that greatly improved the accuracy of quantifying the time-varying probability of conversion to a T1D diagnosis included baseline age, sex, blood glucose measurements from the 120-minute timepoints of oral glucose tolerance tests, and hemoglobin A1c. The developed models represented the underlying evidence to qualify islet AAs as enrichment biomarkers through the qualification of novel methodologies for drug development pathway at the European Medicines Agency (EMA). Additionally, the models are intended as the foundation of a fully functioning end-user tool that will allow sponsors to optimize enrichment criteria for clinical trials in T1D prevention studies.
Asunto(s)
Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Autoanticuerpos/genética , Biomarcadores , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/prevención & control , Hemoglobina Glucada , HumanosRESUMEN
Farmers in Sub-Saharan Africa have lower agricultural technology adoption rates compared to the rest of the world. It is believed that the past season yield affects a farmer's capacity to take on the riskier improved seed variety; but this effect has not been studied. We quantify the effect of past season yield on improved corn seed use in future seasons while addressing the impact of the seed variety on yield. We develop a maximum likelihood method that addresses the fact that farmers self-select into a technology resulting in its effect on yield being endogenous. The method is unique since it models both lagged and endogenous effects in correlated discrete and continuous outcomes simultaneously. Due to the prescence of the lagged effect in a three year dataset, we also propose a solution to the initial conditions problem and demonstrate with simulations its effectiveness. We used survey longitudinal data collected from Kenyan corn farmers for three years. Our results show that higher past season yield increased the likelihood of adoption in future seasons. The simulation and empirical studies indicate that ignoring the self selection of improved seed use biases the results; we obtain a different sign in the covariance.