Control-Relevant Adaptive Personalized Modeling From Limited Clinical Data for Precise Warfarin Management.

Warfarin is a challenging drug to administer due to the narrow therapeutic index of the International Normalized Ratio (INR), the inter- and intra-variability of patients, limited clinical data, genetics, and the effects of other medications. Goal: To predict the optimal warfarin dosage in the presence of the aforementioned challenges, we present an adaptive individualized modeling framework based on model (In)validation and semi-blind robust system identification. The model (In)validation technique adapts the identified individualized patient model according to the change in the patient's status to ensure the model's suitability for prediction and controller design. Results: To implement the proposed adaptive modeling framework, the clinical data of warfarin-INR of forty-four patients has been collected at the Robley Rex Veterans Administration Medical Center, Louisville. The proposed algorithm is compared with recursive ARX and ARMAX model identification methods. The results of identified models using one-step-ahead prediction and minimum mean squared analysis (MMSE) show that the proposed framework effectively predicts the warfarin dosage to keep the INR values within the desired range and adapt the individualized patient model to exhibit the true status of the patient throughout treatment. Conclusion: This paper proposes an adaptive personalized patient modeling framework from limited patientspecific clinical data. It is shown by rigorous simulations that the proposed framework can accurately predict a patient's doseresponse characteristics and it can alert the clinician whenever identified models are no longer suitable for prediction and adapt the model to the current status of the patient to reduce the prediction error.

Adaptive Individualized Drug-Dose Response Modeling from a Limited Clinical Data: Case of Warfarin Management.

Administration of drugs requires sophisticated methods to determine the drug quantity for optimal results, and it has been a challenging task for the number of diseases. To solve these challenges, in this paper, we present the semi-blind robust model identification technique to find individualized patient models using the minimum number of clinically acquired patient-specific data to determine optimal drug dosage. To ensure the usability of these models for dosage predictability and controller design, the model (In)validation technique is also investigated. As a case study, the patients treated with warfarin are studied to demonstrate the semi-blind robust identification and model (In)validation techniques. The performance of models is assessed by calculating minimum means squared error (MMSE).Clinical Relevance- This work establishes a general framework for adaptive individualized drug-dose response models from a limited number of clinical patient-specific data. This work will help clinicians in decision-making for improved drug dosing, patient care, and limiting patient exposure to agents with a narrow therapeutic range.

Precise Warfarin Management through Personalized Modeling and Control with Limited Clinical Data.

Warfarin belongs to a medication class called anticoagulants or blood thinners. It is used for the treatment to prevent blood clots from forming or growing larger. Patients with venous thrombosis, pulmonary embolism, or who have suffered a heart attack, have an irregular heartbeat, or prosthetic heart valves are prescribed with warfarin. It is challenging to find optimal doses due to inter-patient and intra-patient variabilities and narrow therapeutic index. This work presents an individualized warfarin dosing method by utilizing the individual patient model generated using limited clinical data of the patients with chronic conditions under warfarin anticoagulation treatment. Then, the individual precise warfarin dosing is formalized as an optimal control problem, which is solved using the DORBF control approach. The efficiency of the proposed approach is compared with results obtained from practiced clinical protocol.

Redundant feature pruning for accelerated inference in deep neural networks.

This paper presents an efficient technique to reduce the inference cost of deep and/or wide convolutional neural network models by pruning redundant features (or filters). Previous studies have shown that over-sized deep neural network models tend to produce a lot of redundant features that are either shifted version of one another or are very similar and show little or no variations, thus resulting in filtering redundancy. We propose to prune these redundant features along with their related feature maps according to their relative cosine distances in the feature space, thus leading to smaller networks with reduced post-training inference computational costs and competitive performance. We empirically show on select models (VGG-16, ResNet-56, ResNet-110, and ResNet-34) and dataset (MNIST Handwritten digits, CIFAR-10, and ImageNet) that inference costs (in FLOPS) can be significantly reduced while overall performance is still competitive with the state-of-the-art.

Regularizing Deep Neural Networks by Enhancing Diversity in Feature Extraction.

This paper proposes a new and efficient technique to regularize the neural network in the context of deep learning using correlations among features. Previous studies have shown that oversized deep neural network models tend to produce a lot of redundant features that are either the shifted version of one another or are very similar and show little or no variations, thus resulting in redundant filtering. We propose a way to address this problem and show that such redundancy can be avoided using regularization and adaptive feature dropout mechanism. We show that regularizing both negative and positive correlated features according to their differentiation and based on their relative cosine distances yields network extracting dissimilar features with less overfitting and better generalization. This concept is illustrated with deep multilayer perceptron, convolutional neural network, sparse autoencoder, gated recurrent unit, and long short-term memory on MNIST digits recognition, CIFAR-10, ImageNet, and Stanford Natural Language Inference data sets.

Individualized drug dosing using RBF-Galerkin method: Case of anemia management in chronic kidney disease.

BACKGROUND AND OBJECTIVE: Anemia is a common comorbidity in patients with chronic kidney disease (CKD) and is frequently associated with decreased physical component of quality of life, as well as adverse cardiovascular events. Current treatment methods for renal anemia are mostly population-based approaches treating individual patients with a one-size-fits-all model. However, FDA recommendations stipulate individualized anemia treatment with precise control of the hemoglobin concentration and minimal drug utilization. In accordance with these recommendations, this work presents an individualized drug dosing approach to anemia management by leveraging the theory of optimal control. METHODS: A Multiple Receding Horizon Control (MRHC) approach based on the RBF-Galerkin optimization method is proposed for individualized anemia management in CKD patients. Recently developed by the authors, the RBF-Galerkin method uses the radial basis function approximation along with the Galerkin error projection to solve constrained optimal control problems numerically. The proposed approach is applied to generate optimal dosing recommendations for individual patients. RESULTS: Performance of the proposed approach (MRHC) is compared in silico to that of a population-based anemia management protocol and an individualized multiple model predictive control method for two case scenarios: hemoglobin measurement with and without observational errors. In silico comparison indicates that hemoglobin concentration with MRHC method has less variation among the methods, especially in presence of measurement errors. In addition, the average achieved hemoglobin level from the MRHC is significantly closer to the target hemoglobin than that of the other two methods, according to the analysis of variance (ANOVA) statistical test. Furthermore, drug dosages recommended by the MRHC are more stable and accurate and reach the steady-state value notably faster than those generated by the other two methods. CONCLUSIONS: The proposed method is highly efficient for the control of hemoglobin level, yet provides accurate dosage adjustments in the treatment of CKD anemia.

Individualized model discovery: the case of anemia patients.

The universal sequel to chronic kidney condition (CKD) is anemia. Patients of anemia have kidneys that are incapable of performing certain basic functions such as sensing of oxygen levels to secrete erythropoietin when red blood cell counts are low. Under such conditions, external administration of human recombinant erythropoietin (EPO) is administered as alternative to improve conditions of CKD patients by increasing their hemoglobin (Hb) levels to a given therapeutic range. Presently, EPO dosing strategies extensively depend on packet inserts and on "average" responses to the medication from previous patients. Clearly dosage strategies based on these approaches are, at best, nonoptimal to EPO medication and potentially dangerous to patients that do not adhere to the notion of expected "average" response. In this work, a technique called semi-blind robust identification is provided to uniquely identify models of the individual patients of anemia based on their actual Hb responses and EPO administration. Using the a priori information and the measured input-output data of the individual patients, the procedure identifies a unique model consisting of a nominal model and the associated model uncertainty for the patients. By incorporating the effects of unknown system initial conditions, considerably small measurement samples can be used in the modeling process.

Shape analysis of the human brain: a brief survey.

The survey outlines and compares popular computational techniques for quantitative description of shapes of major structural parts of the human brain, including medial axis and skeletal analysis, geodesic distances, Procrustes analysis, deformable models, spherical harmonics, and deformation morphometry, as well as other less widely used techniques. Their advantages, drawbacks, and emerging trends, as well as results of applications, in particular, for computer-aided diagnostics, are discussed.