Computational speed-up of large-scale, single-cell model simulations via a fully integrated SBML-based format.

Summary: Large-scale and whole-cell modeling has multiple challenges, including scalable model building and module communication bottlenecks (e.g. between metabolism, gene expression, signaling, etc.). We previously developed an open-source, scalable format for a large-scale mechanistic model of proliferation and death signaling dynamics, but communication bottlenecks between gene expression and protein biochemistry modules remained. Here, we developed two solutions to communication bottlenecks that speed-up simulation by ∼4-fold for hybrid stochastic-deterministic simulations and by over 100-fold for fully deterministic simulations. Fully deterministic speed-up facilitates model initialization, parameter estimation and sensitivity analysis tasks. Availability and implementation: Source code is freely available at https://github.com/birtwistlelab/SPARCED/releases/tag/v1.3.0 implemented in python, and supported on Linux, Windows and MacOS (via Docker).

A physical activity-intensity driven glycemic model for type 1 diabetes.

BACKGROUND AND OBJECTIVE: The glucose response to physical activity for a person with type 1 diabetes (T1D) depends upon the intensity and duration of the physical activity, plasma insulin concentrations, and the individual physical fitness level. To accurately model the glycemic response to physical activity, these factors must be considered. METHODS: Several physiological models describing the glycemic response to physical activity are proposed by incorporating model terms proportional to the physical activity intensity and duration describing endogenous glucose production (EGP), glucose utilization, and glucose transfer from the plasma to tissues. Leveraging clinical data of T1D during physical activity, each model fit is assessed. RESULTS: The proposed model with terms accommodating EGP, glucose transfer, and insulin-independent glucose utilization allow for an improved simulation of physical activity glycemic responses with the greatest reduction in model error (mean absolute percentage error: 16.11 ± 4.82 vs. 19.49 ± 5.87, p = 0.002). CONCLUSIONS: The development of a physiologically plausible model with model terms representing each major contributor to glucose metabolism during physical activity can outperform traditional models with physical activity described through glucose utilization alone. This model accurately describes the relation of plasma insulin and physical activity intensity on glucose production and glucose utilization to generate the appropriately increasing, decreasing or stable glucose response for each physical activity condition. The proposed model will enable the in silico evaluation of automated insulin dosing algorithms designed to mitigate the effects of physical activity with the appropriate relationship between the reduction in basal insulin and the corresponding glycemic excursion.

Incorporating Prior Information in Adaptive Model Predictive Control for Multivariable Artificial Pancreas Systems.

BACKGROUND: Adaptive model predictive control (MPC) algorithms that recursively update the glucose prediction model are shown to be promising in the development of fully automated multivariable artificial pancreas systems. However, the recursively updated glycemic prediction models do not explicitly consider prior knowledge in the identification of the model parameters. Prior information of the glycemic effects of meals and physical activity can improve model accuracy and yield better glycemic control algorithms. METHODS: A glucose prediction model based on regularized partial least squares (rPLS) method where the prior information is encoded as the regularization term is developed to provide accurate predictions of the future glucose concentrations. An adaptive MPC is developed that incorporates dynamic trajectories for the glucose setpoint and insulin dosing constraints based on the estimated plasma insulin concentration (PIC). The proposed adaptive MPC algorithm is robust to disturbances caused by unannounced meals and physical activities even in cases with missing glucose measurements. The effectiveness of the proposed adaptive MPC based on rPLS is investigated with in silico subjects of the multivariable glucose-insulin-physiological variables simulator (mGIPsim). RESULTS: The efficacy of the proposed adaptive MPC strategy in regulating the blood glucose concentration (BGC) of people with T1DM is assessed using the average percent time in range (TIR) for glucose, defined as 70 to 180 mg/dL inclusive, and the average percent time in hypoglycemia (<70 and >54 mg/dL) and level 2 hypoglycemia (≤54 mg/dL). The TIR for a cohort of 20 virtual subjects of mGIPsim is 81.9% ± 7.4% (with no hypoglycemia or severe hypoglycemia) for the proposed MPC compared with 73.9% ± 7.6% (0.2% ± 0.1% in hypoglycemia and 0.1% ± 0.1% in level 2 hypoglycemia) for an MPC based on a recursive autoregressive exogenous (ARX) model. CONCLUSIONS: The adaptive MPC algorithm that incorporates prior knowledge in the recursive updating of the glucose prediction model can contribute to the development of fully automated artificial pancreas systems that can mitigate meal and physical activity disturbances.

AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models.

The AlphaFold Protein Structure Database (AlphaFold DB, https://alphafold.ebi.ac.uk) is an openly accessible, extensive database of high-accuracy protein-structure predictions. Powered by AlphaFold v2.0 of DeepMind, it has enabled an unprecedented expansion of the structural coverage of the known protein-sequence space. AlphaFold DB provides programmatic access to and interactive visualization of predicted atomic coordinates, per-residue and pairwise model-confidence estimates and predicted aligned errors. The initial release of AlphaFold DB contains over 360,000 predicted structures across 21 model-organism proteomes, which will soon be expanded to cover most of the (over 100 million) representative sequences from the UniRef90 data set.

Observational Study of Glycemic Impact of Anticipatory and Early-Race Athletic Competition Stress in Type 1 Diabetes.

Athletic competitions and the associated psychological stress are a challenge for people with type 1 diabetes (T1D). This study aims to understand the influence of anticipatory and early race competition stress on blood glucose concentrations and to identify personality, demographic, or behavioral traits indicative in the scope of the impact. Ten recreational athletes with T1D competed in an athletic competition and an exercise-intensity matched non-competition "training" session for comparison. The two hours prior to exercise and the first 30 minutes of exercise were compared between the paired exercise sessions to assess the influence of anticipatory and early race stress. The effectiveness index, average CGM glucose, and the ingested carbohydrate to injected insulin ratio were compared between the paired sessions through regression. In 9 of 12 races studied, an elevated CGM for the race over the individual training session was observed. The rate of change of the CGM during the first 30 minutes of exercise notably differed between the race and training (p = 0.02) with a less rapid decline in CGM occurring during the race for 11 of 12 paired sessions and an increasing CGM trend during the race for 7 of the 12 sessions with the rate of change (mean ± standard deviation) as 1.36 ± 6.07 and -2.59 ± 2.68 mg/dL per 5 minutes for the race and training, respectively. Individuals with longer durations of diabetes often decreased their carbohydrate-to-insulin ratio on race day, taking more insulin, than on the training day while the reverse was noted for those newly diagnosed (r = -0.52, p = 0.05). The presence of athletic competition stress can impact glycemia. With an increasing duration of diabetes, the athletes may be expecting elevated competition glucose concentrations and take preventive measures.

Prior Informed Regularization of Recursively Updated Latent-Variables-Based Models with Missing Observations.

Many data-driven modeling techniques identify locally valid, linear representations of time-varying or nonlinear systems, and thus the model parameters must be adaptively updated as the operating conditions of the system vary, though the model identification typically does not consider prior knowledge. In this work, we propose a new regularized partial least squares (rPLS) algorithm that incorporates prior knowledge in the model identification and can handle missing data in the independent covariates. This latent variable (LV) based modeling technique consists of three steps. First, a LV-based model is developed on the historical time series data. In the second step, the missing observations in the new incomplete data sample are estimated. Finally, the future values of the outputs are predicted as a linear combination of estimated scores and loadings. The model is recursively updated as new data are obtained from the system. The performance of the proposed rPLS and rPLS with exogenous inputs (rPLSX) algorithms are evaluated by modeling variations in glucose concentration (GC) of people with Type 1 diabetes (T1D) in response to meals and physical activities for prediction windows up to one hour, or 12 sampling instances, into the future. The proposed rPLS family of GC prediction models are evaluated with both in-silico and clinical experiment data and compared with the performance of recursive time series and kernel-based models. The root mean squared error (RMSE) with simulated subjects in the multivariable T1D simulator where physical activity effects are incorporated in GC variations are 2.52 and 5.81 mg/dL for 30 and 60 mins ahead predictions (respectively) when information for all meals and physical activities are used, increasing to 2.70 and 6.54 mg/dL (respectively) when meals and activities occurred, but the information is with-held from the modeling algorithms. The RMSE is 10.45 and 14.48 mg/dL for clinical study with prediction horizons of 30 and 60 mins, respectively. The low RMSE values demonstrate the effectiveness of the proposed rPLS approach compared to the conventional recursive modeling algorithms.

Discrimination of simultaneous psychological and physical stressors using wristband biosignals.

BACKGROUND AND OBJECTIVE: In this work, we address the problem of detecting and discriminating acute psychological stress (APS) in the presence of concurrent physical activity (PA) using wristband biosignals. We focused on signals available from wearable devices that can be worn in daily life because the ultimate objective of this work is to provide APS and PA information in real-time management of chronic conditions such as diabetes by automated personalized insulin delivery. Monitoring APS noninvasively throughout free-living conditions remains challenging because the responses to APS and PA of many physiological variables measured by wearable devices are similar. METHODS: Various classification algorithms are compared to simultaneously detect and discriminate the PA (sedentary state, treadmill running, and stationary bike) and the type of APS (non-stress state, mental stress, and emotional anxiety). The impact of APS inducements is verified with commonly used self-reported questionnaires (The State-Trait Anxiety Inventory (STAI)). To aid the classification algorithms, novel features are generated from the physiological variables reported by a wristband device during 117 hours of experiments involving simultaneous APS inducement and PA. We also translate the APS assessment into a quantitative metric for use in predicting the adverse outcomes. RESULTS: An accurate classification of the concurrent PA and APS states is achieved with an overall classification accuracy of 99% for PA and 92% for APS. The average accuracy of APS detection during sedentary state, treadmill running, and stationary bike is 97.3, 94.1, and 84.5%, respectively. CONCLUSIONS: The simultaneous assessment of APS and PA throughout free-living conditions from a convenient wristband device is useful for monitoring the factors contributing to an elevated risk of acute events in people with chronic diseases like cardiovascular complications and diabetes.

Determining Physical Activity Characteristics from Wristband Data for Use in Automated Insulin Delivery Systems.

Algorithms that can determine the type of physical activity (PA) and quantify the intensity can allow precision medicine approaches, such as automated insulin delivery systems that modulate insulin administration in response to PA. In this work, data from a multi-sensor wristband is used to design classifiers to distinguish among five different physical states (PS) (resting, activities of daily living, running, biking, and resistance training), and to develop models to estimate the energy expenditure (EE) of the PA for diabetes therapy. The data collected are filtered, features are extracted from the reconciled signals, and the extracted features are used by machine learning algorithms, including deep-learning techniques, to obtain accurate PS classification and EE estimation. The various machine learning techniques have different success rates ranging from 75.7% to 94.8% in classifying the five different PS. The deep neural network model with long short-term memory has 94.8% classification accuracy. We achieved 0.5 MET (Metabolic Equivalent of Task) root-mean-square error for EE estimation accuracy, relative to indirect calorimetry with randomly selected testing data (10% of collected data). We also demonstrate a 5% improvement in PS classification accuracy and a 0.34 MET decrease in the mean absolute error when using multi-sensor approach relative to using only accelerometer data.

Online Glucose Prediction Using Computationally Efficient Sparse Kernel Filtering Algorithms in Type-1 Diabetes.

Streaming data from continuous glucose monitoring (CGM) systems enable the recursive identification of models to improve estimation accuracy for effective predictive glycemic control in patients with type-1 diabetes. A drawback of conventional recursive identification techniques is the increase in computational requirements, which is a concern for online and real-time applications such as the artificial pancreas systems implemented on handheld devices and smartphones where computational resources and memory are limited. To improve predictions in such computationally constrained hardware settings, efficient adaptive kernel filtering algorithms are developed in this paper to characterize the nonlinear glycemic variability by employing a sparsification criterion based on the information theory to reduce the computation time and complexity of the kernel filters without adversely deteriorating the predictive performance. Furthermore, the adaptive kernel filtering algorithms are designed to be insensitive to abnormal CGM measurements, thus compensating for measurement noise and disturbances. As such, the sparsification-based real-time model update framework can adapt the prediction models to accurately characterize the time-varying and nonlinear dynamics of glycemic measurements. The proposed recursive kernel filtering algorithms leveraging sparsity for improved computational efficiency are applied to both in-silico and clinical subjects, and the results demonstrate the effectiveness of the proposed methods.

Controlling the AP Controller: Controller Performance Assessment and Modification.

BACKGROUND: Despite recent advances in closed-loop control of blood glucose concentration (BGC) in people with type 1 diabetes (T1D), online performance assessment and modification of artificial pancreas (AP) control systems remain a challenge as the metabolic characteristics of users change over time. METHODS: A controller performance assessment and modification system (CPAMS) analyzes the glucose concentration variations and controller behavior, and modifies the parameters of the control system used in the multivariable AP system. Various indices are defined to quantitatively evaluate the controller performance in real time. Controller performance assessment and modification system also incorporates online learning from historical data to anticipate impending disturbances and proactively counteract their effects. RESULTS: Using a multivariable simulation platform for T1D, the CPAMS is used to enhance the BGC regulation in people with T1D by means of automated insulin delivery with an adaptive learning predictive controller. Controller performance assessment and modification system increases the percentage of time in the target range (70-180) mg/dL by 52.3% without causing any hypoglycemia and hyperglycemia events. CONCLUSIONS: The results demonstrate a significant improvement in the multivariable AP controller performance by using CPAMS.

Multi-Model Sensor Fault Detection and Data Reconciliation: A Case Study with Glucose Concentration Sensors for Diabetes.

Erroneous information from sensors affect process monitoring and control. An algorithm with multiple model identification methods will improve the sensitivity and accuracy of sensor fault detection and data reconciliation (SFD&DR). A novel SFD&DR algorithm with four types of models including outlier robust Kalman filter, locally weighted partial least squares, predictor-based subspace identification, and approximate linear dependency-based kernel recursive least squares is proposed. The residuals are further analyzed by artificial neural networks and a voting algorithm. The performance of the SFD&DR algorithm is illustrated by clinical data from artificial pancreas experiments with people with diabetes. The glucose-insulin metabolism has time-varying parameters and nonlinearities, providing a challenging system for fault detection and data reconciliation. Data from 17 clinical experiments collected over 896 hours were analyzed; the results indicate that the proposed SFD&DR algorithm is capable of detecting and diagnosing sensor faults and reconciling the erroneous sensor signals with better model-estimated values.

Improving Glucose Prediction Accuracy in Physically Active Adolescents With Type 1 Diabetes.

BACKGROUND: Physical activity presents a significant challenge for glycemic control in individuals with type 1 diabetes. As accurate glycemic predictions are key to successful automated decision-making systems (eg, artificial pancreas, AP), the inclusion of additional physiological variables in the estimation of the metabolic state may improve the glucose prediction accuracy during exercise. METHODS: Predictor-based subspace identification is applied to a dynamic glucose prediction model including heart rate measurements along with variables representing the carbohydrate consumption and insulin boluses. To demonstrate the improvement in prediction ability due to the additional heart rate variable, the performance of the proposed modeling technique is evaluated with (SID-HR) and without heart rate (SID-2) as an additional input using experimental data involving adolescents at ski camp. Furthermore, the performance of the proposed approach is compared to that of the metabolic state observer (MSO) model currently used in the University of Virginia AP algorithm. RESULTS: The addition of heart rate in the subspace-based model (SID-HR) yields a statistically significant improvement in the root-mean-square error compared to the SID-2 model (P < .001) and the standard MSO (P < .001). Furthermore, the SID-HR model performed favorably in comparison to the SID-2 and MSO models after accounting for its increased complexity. CONCLUSIONS: Directly considering the effects of physical activity levels on glycemic dynamics through the inclusion of heart rate as an additional input variable in the glucose dynamics model improves the glucose prediction accuracy. The proposed methodology could improve exercise-informed model-based predictive control algorithms in artificial pancreas systems.

Simulation Software for Assessment of Nonlinear and Adaptive Multivariable Control Algorithms: Glucose - Insulin Dynamics in Type 1 Diabetes.

A simulator for testing automatic control algorithms for nonlinear systems with time-varying parameters, variable time delays, and uncertainties is developed. It is based on simulation of virtual patients with Type 1 diabetes (T1D). Nonlinear models are developed to describe glucose concentration (GC) variations based on user-defined scenarios for meal consumption, insulin administration, and physical activity. They compute GC values and physiological variables, such as heart rate, skin temperature, accelerometer, and energy expenditure, that are indicative of physical activities affecting GC dynamics. This is the first simulator designed for assessment of multivariable controllers that consider supplemental physiological variables in addition to GC measurements to improve glycemic control. Virtual patients are generated from distributions of identified model parameters using clinical data. The simulator will enable testing and evaluation of new control algorithms proposed for automated insulin delivery as well as various control algorithms for nonlinear systems with uncertainties, time-varying parameters and delays.

Multi-level Supervision and Modification of Artificial Pancreas Control System.

Artificial pancreas (AP) systems provide automated regulation of blood glucose concentration (BGC) for people with type 1 diabetes (T1D). An AP includes three components: a continuous glucose monitoring (CGM) sensor, a controller calculating insulin infusion rate based on the CGM signal, and a pump delivering the insulin amount calculated by the controller to the patient. The performance of the AP system depends on successful operation of these three components. Many APs use model predictive controllers that rely on models to predict BGC and to calculate the optimal insulin infusion rate. The performance of model-based controllers depends on the accuracy of the models that is affected by large dynamic changes in glucose-insulin metabolism or equipment performance that may move the operating conditions away from those used in developing the models and designing the control system. Sensor errors and missing signals will cause calculation of erroneous insulin infusion rates. And the performance of the controller may vary at each sampling step and each period (meal, exercise, and sleep), and from day to day. Here we describe a multi-level supervision and controller modification (ML-SCM) module is developed to supervise the performance of the AP system and retune the controller. It supervises AP performance in 3 time windows: sample level, period level, and day level. At sample level, an online controller performance assessment sub-module will generate controller performance indexes to evaluate various components of the AP system and conservatively modify the controller. A sensor error detection and signal reconciliation module will detect sensor error and reconcile the CGM sensor signal at each sample. At period level, the controller performance is evaluated with information collected during a certain time period and the controller is tuned more aggressively. At the day level, the daily CGM ranges are further analyzed to determine the adjustable range of controller parameters used for sample level and period level. Thirty subjects in the UVa/Padova metabolic simulator were used to evaluate the performance of the ML-SCM module and one clinical experiment is used to illustrate its performance in a clinical environment. The results indicate that the AP system with an ML-SCM module has a safer range of glucose concentration distribution and more appropriate insulin infusion rate suggestions than an AP system without the ML-SCM module.

Multivariable Artificial Pancreas for Various Exercise Types and Intensities.

BACKGROUND: Exercise challenges people with type 1 diabetes in controlling their glucose concentration (GC). A multivariable adaptive artificial pancreas (MAAP) may lessen the burden. METHODS: The MAAP operates without any user input and computes insulin based on continuous glucose monitor and physical activity signals. To analyze performance, 18 60-h closed-loop experiments with 96 exercise sessions with three different protocols were completed. Each day, the subjects completed one resistance and one treadmill exercise (moderate continuous training [MCT] or high-intensity interval training [HIIT]). The primary outcome is time spent in each glycemic range during the exercise + recovery period. Secondary measures include average GC and average change in GC during each exercise modality. RESULTS: The GC during exercise + recovery periods were within the euglycemic range (70-180 mg/dL) for 69.9% of the time and within a safe glycemic range for exercise (70-250 mg/dL) for 93.0% of the time. The exercise sessions are defined to begin 30 min before the start of exercise and end 2 h after start of exercise. The GC were within the severe hypoglycemia (<55 mg/dL), moderate hypoglycemia (55-70 mg/dL), moderate hyperglycemia (180-250 mg/dL), and severe hyperglycemia (>250 mg/dL) for 0.9%, 1.3%, 23.1%, and 4.8% of the time, respectively. The average GC decline during exercise differed with exercise type (P = 0.0097) with a significant difference between the MCT and resistance (P = 0.0075). To prevent large GC decreases leading to hypoglycemia, MAAP recommended carbohydrates in 59% of MCT, 50% of HIIT, and 39% of resistance sessions. CONCLUSIONS: A consistent GC decline occurred in exercise and recovery periods, which differed with exercise type. The average GC at the start of exercise was above target (185.5 ± 56.6 mg/dL for MCT, 166.9 ± 61.9 mg/dL for resistance training, and 171.7 ± 41.4 mg/dL HIIT), making a small decrease desirable. Hypoglycemic events occurred in 14.6% of exercise sessions and represented only 2.22% of the exercise and recovery period.

Incorporating Unannounced Meals and Exercise in Adaptive Learning of Personalized Models for Multivariable Artificial Pancreas Systems.

BACKGROUND: Despite the recent advancements in the modeling of glycemic dynamics for type 1 diabetes mellitus, automatically considering unannounced meals and exercise without manual user inputs remains challenging. METHOD: An adaptive model identification technique that incorporates exercise information and estimates of the effects of unannounced meals obtained automatically without user input is proposed in this work. The effects of the unknown consumed carbohydrates are estimated using an individualized unscented Kalman filtering algorithm employing an augmented glucose-insulin dynamic model, and exercise information is acquired from noninvasive physiological measurements. The additional information on meals and exercise is incorporated with personalized estimates of plasma insulin concentration and glucose measurement data in an adaptive model identification algorithm. RESULTS: The efficacy of the proposed personalized and adaptive modeling algorithm is demonstrated using clinical data involving closed-loop experiments of the artificial pancreas system, and the results demonstrate accurate glycemic modeling with the average root-mean-square error (mean absolute error) of 25.50 mg/dL (18.18 mg/dL) for six-step (30 minutes ahead) predictions. CONCLUSIONS: The approach presented is able to identify reliable time-varying individualized glucose-insulin models.

Adaptive and Personalized Plasma Insulin Concentration Estimation for Artificial Pancreas Systems.

BACKGROUND: The artificial pancreas (AP) system, a technology that automatically administers exogenous insulin in people with type 1 diabetes mellitus (T1DM) to regulate their blood glucose concentrations, necessitates the estimation of the amount of active insulin already present in the body to avoid overdosing. METHOD: An adaptive and personalized plasma insulin concentration (PIC) estimator is designed in this work to accurately quantify the insulin present in the bloodstream. The proposed PIC estimation approach incorporates Hovorka's glucose-insulin model with the unscented Kalman filtering algorithm. Methods for the personalized initialization of the time-varying model parameters to individual patients for improved estimator convergence are developed. Data from 20 three-days-long closed-loop clinical experiments conducted involving subjects with T1DM are used to evaluate the proposed PIC estimation approach. RESULTS: The proposed methods are applied to the clinical data containing significant disturbances, such as unannounced meals and exercise, and the results demonstrate the accurate real-time estimation of the PIC with the root mean square error of 7.15 and 9.25 mU/L for the optimization-based fitted parameters and partial least squares regression-based testing parameters, respectively. CONCLUSIONS: The accurate real-time estimation of PIC will benefit the AP systems by preventing overdelivery of insulin when significant insulin is present in the bloodstream.

Automatic Detection and Estimation of Unannounced Meals for Multivariable Artificial Pancreas System.

BACKGROUND: Automatically attenuating the postprandial rise in the blood glucose concentration without manual meal announcement is a significant challenge for artificial pancreas (AP) systems. In this study, a meal module is proposed to detect the consumption of a meal and to estimate the amount of carbohydrate (CHO) intake. METHODS: The meals are detected based on qualitative variables describing variation of continuous glucose monitoring (CGM) readings. The CHO content of the meals/snacks is estimated by a fuzzy system using CGM and subcutaneous insulin delivery data. The meal bolus amount is computed according to the patient's insulin to CHO ratio. Integration of the meal module into a multivariable AP system allows revision of estimated CHO based on knowledge about physical activity, sleep, and the risk of hypoglycemia before the final decision for a meal bolus is made. RESULTS: The algorithm is evaluated by using 117 meals/snacks in retrospective data from 11 subjects with type 1 diabetes. Sensitivity, defined as the percentage of correctly detected meals and snacks, is 93.5% for meals and 68.0% for snacks. The percentage of false positives, defined as the proportion of false detections relative to the total number of detected meals and snacks, is 20.8%. CONCLUSIONS: Integration of a meal detection module in an AP system is a further step toward an automated AP without manual entries. Detection of a consumed meal/snack and infusion of insulin boluses using an estimate of CHO enables the AP system to automatically prevent postprandial hyperglycemia.

The National Institutes of Health Fogarty International Center Global Health Scholars and Fellows Program: Collaborating Across Five Consortia to Strengthen Research Training.

As demand for global health research training continues to grow, many universities are striving to meet the needs of trainees in a manner complementary to research priorities of the institutions hosting trainees, while also increasing capacity for conducting research. We provide an overview of the first 4 years of the Global Health Program for Fellows and Scholars, a collaboration of 20 U.S. universities and institutions spread across 36 low- and middle-income countries funded through the National Institutes of Health Fogarty International Center. We highlight many aspects of our program development that may be of interest to other multinational consortia developing global health research training programs.

The development and implementation of a competency-based curriculum for training in global health research.

The Fogarty International Center (FIC) Global Health Fellows Program provides trainees with the opportunity to develop research skills through a mentored research experience, increase their content expertise, and better understand trends in global health research, funding organizations, and pathways to generate support. The Northern Pacific Global Health Fellows Research and Training Consortium, which hosts one of the FIC Global Health Programs, sought to enhance research training by developing, implementing, and evaluating a competency-based curriculum that uses a modular, asynchronous, web-based format. The curriculum has 8 core competencies, 36 learning objectives, and 58 assignments. Nineteen trainees completed their 11-month fellowship, engaged in the curriculum, and provided pre- and post-fellowship self-assessments. Self-assessed scores significantly improved for all competencies. Trainees identified the curriculum as one of the strengths of the program. This competency-based curriculum represents a first step toward creating a framework of global health research competencies on which further efforts could be based.