An integrated methodology to control the risk of cardiovascular disease in patients with hypertension and type 1 diabetes

Today, air pollution, smoking, use of fatty acids and ready‐made foods, and so on, have exacerbated heart disease. Therefore, controlling the risk of such diseases can prevent or reduce their incidence. The present study aimed at developing an integrated methodology including Markov decision processes (MDP) and genetic algorithm (GA) to control the risk of cardiovascular disease in patients with hypertension and type 1 diabetes. First, the efficiency of GA is evaluated against Grey Wolf optimization (GWO) algorithm, and then, the superiority of GA is revealed. Next, the MDP is employed to estimate the risk of cardiovascular disease. For this purpose, model inputs are first determined using a validated micro‐simulation model for screening cardiovascular disease developed at Tehran University of Medical Sciences, Iran by GA. The model input factors are then defined accordingly and using these inputs, three risk estimation models are identified. The results of these models support WHO guidelines that provide medicine with a high discount to patients with high expected LYs. To develop the MDP methodology, policies should be adopted that work well despite the difference between the risk model and the actual risk. Finally, a sensitivity analysis is conducted to study the behavior of the total medication cost against the changes of parameters.     

Development of a multi-parametric model predictive control algorithm for insulin delivery in type 1 diabetes mellitus using clinical parameters

A multi-parametric model predictive control (mpMPC) algorithm for subcutaneous insulin delivery for individuals with type 1 diabetes mellitus (T1DM) that is computationally efficient, robust to variations in insulin sensitivity, and involves minimal burden for the user is proposed. System identification was achieved through impulse response tests feasible for ambulatory conditions on the UVa/Padova simulator adult subjects with T1DM. An alternative means of system identification using readily available clinical parameters was also investigated. A safety constraint was included explicitly in the algorithm formulation using clinical parameters typical of those available to an attending physician. Closed-loop simulations were carried out with daily consumption of 200 g carbohydrate. Controller robustness was assessed by subject/model mismatch scenarios addressing daily, simultaneous variation in insulin sensitivity and meal size with the addition of Gaussian white noise with a standard deviation of 10%. A second-order-plus-time-delay transfer function model fit the validation data with a mean (coefficient of variation) root-mean-square-error (RMSE) of 26 mg/dL (19%) for a 3 h prediction horizon. The resulting control law maintained a low risk Low Blood Glucose Index without any information about carbohydrate consumption for 90% of the subjects. Low-order linear models with clinically meaningful parameters thus provided sufficient information for a model predictive control algorithm to control glycemia. The use of clinical knowledge as a safety constraint can reduce hypoglycemic events, and this same knowledge can further improve glycemic control when used explicitly as the controller model. The resulting mpMPC algorithm was sufficiently compact to be implemented on a simple electronic device.     

Continuous-time interval model identification of blood glucose dynamics for type 1 diabetes

While good physiological models of the glucose metabolism in type 1 diabetic patients are well known, their parameterisation is difficult. The high intra-patient variability observed is a further major obstacle. This holds for data-based models too, so that no good patient-specific models are available. Against this background, this paper proposes the use of interval models to cover the different metabolic conditions. The control-oriented models contain a carbohydrate and insulin sensitivity factor to be used for insulin bolus calculators directly. Available clinical measurements were sampled on an irregular schedule which prompts the use of continuous-time identification, also for the direct estimation of the clinically interpretable factors mentioned above. An identification method is derived and applied to real data from 28 diabetic patients. Model estimation was done on a clinical data-set, whereas validation results shown were done on an out-of-clinic, everyday life data-set. The results show that the interval model approach allows a much more regular estimation of the parameters and avoids physiologically incompatible parameter estimates.     

Experimental blood glucose interval identification of patients with type 1 diabetes

Many problems are confronted when characterizing a type 1 diabetic patient such as model mismatches, noisy inputs, measurement errors and huge variability in the glucose profiles. In this work we introduce a new identification method based on interval analysis where variability and model imprecisions are represented by an interval model as parametric uncertainty.The minimization of a composite cost index comprising: (1) the glucose envelope width predicted by the interval model, and (2) a Hausdorff-distance-based prediction error with respect to the envelope, is proposed. The method is evaluated with clinical data consisting in insulin and blood glucose reference measurements from 12 patients for four different lunchtime postprandial periods each.Following a “leave-one-day-out” cross-validation study, model prediction capabilities for validation days were encouraging (medians of: relative error = 5.45%, samples predicted = 57%, prediction width = 79.1 mg/dL). The consideration of the days with maximum patient variability represented as identification days, resulted in improved prediction capabilities for the identified model (medians of: relative error = 0.03%, samples predicted = 96.8%, prediction width = 101.3 mg/dL). Feasibility of interval models identification in the context of type 1 diabetes was demonstrated.     

Comparative assessment of statistical and machine learning techniques towards estimating the risk of developing type 2 diabetes and cardiovascular complications

The aim of the present study is to comparatively assess the performance of different machine learning and statistical techniques with regard to their ability to estimate the risk of developing type 2 diabetes mellitus (Case 1) and cardiovascular disease complications (Case 2). This is the first work investigating the application of ensembles of artificial neural networks (EANN) towards producing the 5‐year risk of developing type 2 diabetes mellitus and cardiovascular disease as a long‐term diabetes complication. The performance of the proposed models has been comparatively assessed with the performance obtained by applying logistic regression, Bayesian‐based approaches, and decision trees. The models' discrimination and calibration have been evaluated using the classification accuracy (ACC), the area under the curve (AUC) criterion, and the Hosmer–Lemeshow goodness of fit test. The obtained results demonstrate the superiority of the proposed models (EANN) over the other models. In Case 1, EANN with different topologies has achieved high discrimination and good calibration performance (ACC = 80.20%, AUC = 0.849, p value = .886). In Case 2, EANN based on bagging has resulted in good discrimination and calibration performance (ACC = 92.86%, AUC = 0.739, p value = .755).     

Comparison of interval and Monte Carlo simulation for the prediction of postprandial glucose under uncertainty in type 1 diabetes mellitus

In this paper, the problem of tackling uncertainty in the prediction of postprandial blood glucose is analyzed. Two simulation approaches, Monte Carlo and interval models, are studied and compared. Interval simulation is carried out using modal interval analysis. Simulation of a glucoregulatory model with uncertainty in insulin sensitivities, glucose absorption and food intake is carried out using both methods. Interval simulation is superior in predicting all severe and mild hyper- and hypoglycemia episodes. Furthermore, much less computational time is required for interval simulation than for Monte Carlo simulation.     

数据挖掘在2型糖尿病数据处理中的应用

基于大量实测数据探索2型糖尿病的发病规律,寻求其有效的数据处理方法。将数据挖掘技术引入到2型糖尿病数据处理中得出决策分类树,再同医学认识相对照。利用11400条实测数据,采用C4．5算法得出分类树,经实验患病人群的正确识别率为80．90％,未患病人群的正确识别率为92．05％。给出的决策分类树同目前医学上认识的高危因素趋于一致,同时给出了血糖值等于5．85的临界性数值。数据挖掘方法的引入为2型糖尿病数据处理提供了一种新的方法,为其预警、干预和有效控制提供了一种新的解决方案。     

Abnormal cytoskeletal protein expression in cultured skin fibroblasts from type 1 diabetes mellitus patients with nephropathy: A proteomic approach

Diabetic nephropathy (DN) develops in about 40% of insulin-dependent type 1 diabetes mellitus (T1DM) patients, and is associated not only with diabetes duration and metabolic control, but also with a genetic predisposition. Constitutive alterations of cytoskeletal proteins may play a role in the development of DN. We investigated the expression of these proteins in cultured skin fibroblasts, obtained from long-term T1DM patients with and without DN but comparable metabolic control, and from matched healthy subjects, by means of 2-DE electrophoresis and MS-MALDI analyses. In T1DM with DN, compared to the other two groups, quantitative analyses revealed an altered expression of 17 spots (p<0.05-p<0.01), corresponding to 12 unique proteins. In T1DM with DN, beta-actin and three isoforms of tubulin beta-2 chain, tropomodulin-3, and LASP-1 were decreased, whereas two tubulin beta-4 chain isoforms, one alpha actinin-4 isoform, membrane-organizing extension spike protein (MOESIN), FLJ00279 (corresponding to a fragment of myosin heavy chain, non-muscle type A), vinculin, a tropomyosin isoform, and the macrophage capping protein were increased. A shift in caldesmon isoforms was also detected. These results demonstrate an association between DN and the constitutive expression of cytoskeleton proteins in cultured skin fibroblasts from T1DM with DN, which may retain pathophysiologycal implications.     

Feedback and feedforward control in the context of model predictive control with application to the management of type 1 diabetes mellitus

A unified formulation of feedback and feedforward control is given in the context of model predictive control. The ideas are illustrated by the management of type 1 diabetes mellitus although the general principles apply, mutatis mutandis, to other scenarios and problems.     

Evaluation of a type 1 diabetes serum cohort by SELDI-TOF MS protein profiling

Proteomics analysis of serum from patients with type 1 diabetes (T1D) may lead to novel biomarkers for prediction of disease and for patient monitoring. However, the serum proteome is highly sensitive to sample processing and before proteomics biomarker research serum cohorts should preferably be examined for potential bias between sample groups. SELDI‐TOF MS protein profiling was used for preliminary evaluation of a biological‐bank with 766 serum samples from 270 patients with T1D, collected at 18 different paediatric centers representing 15 countries in Europe and Japan over 2 years (2000–2002). Samples collected 1 (n = 270), 6 (n = 248), and 12 (n = 248) months after T1D diagnosis were grouped across centers and compared. The serum protein profiles varied with collection site and day of analysis; however, markers of sample processing were not systematically different between samples collected at different times after diagnosis. Three members of the apolipoprotein family increased with time in patient serum collected 1, 6, and 12 months after diagnosis (ANOVA, p<0.001). These results support the use of this serum cohort for further proteomic studies and illustrate the potential of high‐throughput MALDI/SELDI‐TOF MS protein profiling for evaluation of serum cohorts before proteomics biomarker research.     

基于BERT的心血管医疗指南实体关系抽取方法

实体关系抽取是医疗领域知识问答、知识图谱构建及信息抽取的重要基础环节之一。针对在心血管专病知识图谱构建的过程中尚无公开数据集可用的情况,收集了心血管疾病领域的医疗指南并进行相应的实体和关系类别的专业标注,构建了心血管专病知识图谱实体关系抽取的专业数据集。基于该数据集,首先提出双向变形编码器卷积神经网络（BERT-CNN）模型以实现中文语料中的关系抽取,然后根据中文语义中主要以词而不是字为基本单位的特性,提出了改进的基于全词掩模的双向变形编码器卷积神经网络（BERT（wwm）-CNN）模型用于提升在中文语料中关系抽取的性能。实验结果表明,改进的BERT（wwm）-CNN在所构建的关系抽取数据集上准确率达到0.85,召回率达到0.80,F₁值达到0.83,优于对比的基于双向变形编码器长短期记忆网络（BERT-LSTM）模型和BERT-CNN模型,验证了改进网络模型的优势。     

Investigating the binding preferences of small molecule inhibitors of human protein arginine methyltransferase 1 using molecular modelling

Protein arginine methyltransferases (PRMTs) catalyse the methylation of arginine residues of target proteins. PRMTs utilise S-adenosyl methionine (SAM) as the methyl group donor, leading to S-adenosyl homocysteine (SAH) and monomethylarginine (mMA). A combination of homology modelling, molecular docking, Active Site Pressurisation, molecular dynamic simulations and MM-PBSA free energy calculations is used to investigate the binding poses of three PRMT1 inhibitors (ligands 1–3), which target both SAM and substrate arginine binding sites by containing a guanidine group joined by short linkers with the SAM derivative. It was assumed initially that the adenine moieties of the inhibitors would bind in sub-site 1 (PHE44, GLU137, VAL136 and GLU108), the guanidine side chain would occupy sub-site 2 (GLU 161, TYR160, TYR156 and TRP302), with the amino acid side chain occupying sub-site 3 (GLU152, ARG62, GLY86 and ASP84; pose 1). However, the SAH homocysteine moiety does not fully occupy sub-site 3, suggesting another binding pose may exist (pose 2), whereby the adenine moiety binds in sub-site 1, the guanidine side chain occupies sub-site 3, and the amino acid side chain occupies sub-site 2. Our results indicate that ligand 1 (pose 1 or 2), ligand 2 (pose 2) and ligand 3 (pose 1) are the predominant binding poses and we demonstrate for the first time that sub-site 3 contains a large space that could be exploited in the future to develop novel inhibitors with higher binding affinities.