European Journal of Scientific Research ISSN 1450-216X Vol.66 No.2 (2011), pp. 293-302 EuroJournals Publishing, Inc.

. 2011 http://www.europeanjournalofscientificresearch.com

Continuous Glucose Monitoring Sensor Data: Denoising with Hybrid of Neural Network and Extended Kalman Filter Algorithm
S. Shanthi Department of Electronics and Communication Engineering, JJ College of Engineering and Technology, Anna Uinversity of Technology, Tiruchirappalli, Tamilnadu, India E-mail: sshanthijj@gmail.com D. Kumar Dean-Research, Periyaar Maniammai University, Vallam, Tanjore, Tamilnadu, India E-mail: kumar_durai@yahoo.com Abstract Diabetes Mellitus is a chronic disease that has become the third major cause of death around the world. To prevent the adverse effects of diabetes, people use continuous glucose monitoring (CGM) devices. But the accuracy of CGM data is affected with time lag, random fluctuations and noise related with sensor physics and chemistry. These noise effects gives a setback in using the CGM data in generation of Hypo / Hyper glycemic alerts and control signal in artificial pancreas. This paper deals with a hybrid filtering technique (HFT) comprising of an artificial neural network trained with extended Kalman filter algorithm to remove all types of noise in CGM signal. The method has been evaluated with simulated data obtained through Glucosim and validated with the performance metric of Root Mean Square Error. And the method is also compared with moving average and Kalman filter techniques.

Keywords: Continuous Glucose Monitoring, Diabetes , Extended Kalman filter, Neural Network, Noise effects.

1. Introduction
In a recent survey it is found that nearly 250 million people around the world are affected with Diabetes and this number will be in a growing trend every year. This has become a major health issue to be taken care of. Diabetes Mellitus is an auto immune disease due to the inability of the pancreas in secreting sufficient insulin. Insulin is the hormone which facilitates the uptake of glucose from the blood in to the body cells. Shortage of insulin leads to accumulation of glucose in blood (Hyperglycemia) resulting in complications like Diabetic retinopathy, nephropathy and cardio vascular diseases. Excess of insulin leads to lower glucose levels (Hypo glycemia) resulting in Diabetic Coma, Seizures etc To avoid the complications one has to maintain their blood glucose value between 70 120 mg/dL ( Euglycemia or Normo glycemia). Regular monitoring and intensive insulin therapy can help reduce the risks of Diabetes. This paper addresses various types of errors in the continuous glucose monitoring (CGM) data and a solution which can be implemented in CGM devices. As

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discussed earlier, glucose is the important fuel for the humans and its level must be maintained within safe range. For observing the Blood glucose (BG) level , Continuous Glucose Monitoring (CGM) sensors are used[1][2]. The CGM devices can be used for a period of 5 to 7 days and the data stored in it are applied for retrospective analysis. These CGM sensors are of minimally invasive type and are placed in the subcutaneous tissue to measure the Interstitial fluid glucose (IG) rather than BG concentration. There is a time lag of 5 12 minutes for the glucose to traverse from blood to interstitial fluid. [3] The existence of BG to IG kinetics has been described in the literature[4] through a 2 compartmental model. 1 g d ( IG ( t )) / dt = IG ( t ) + BG ( t ) (1)

Where g is the static gain of BG to IG system which is equal to 1 under steady state. is the time lag which can vary between individuals. This BG to IG kinetics acts as a linear low pass filter and introduces a distortion in phase and amplitude as shown in figure 1.
Figure 1: Representative data taken from Kovatchev et al.,

This figure shows a comparison performed in a clinical study [5] on a Type 1 Diabetic subject with BG references collected every 15 minutes and measured in lab by YSI( Yellow Springs ,OH, USA) and with Free Style Navigator CGM profile. The CGM devices try to compensate this time lag by recalibration procedures. Apart from this calibration error, another source of error is the random noise component related to sensor physics. [6][7] Finally the CGM signal is also affected with random fluctuations at high frequency.[8] These noises in sensor output makes the measurement unreliable. These noise components have to be removed prior to any signal processing application. The remaining part of the paper is organized as follows. Section II gives a review of filtering approaches for CGM signal. Section III describes the methodology of the work done. Section IV gives the details of HFT structure and extended Kalman filter algorithm. Section V deals with the experimental part. and the results and discussion. Section VI is the conclusion.

2. Review on Filtering of CGM Signal

Digital filtering techniques can be used to improve the quality of the signal by reducing the random noise components. [9] y ( t ) = g ( t ) + n( t ) (2) Where g ( t ) is the actual signal, n(t ) is the noise added with and y ( t ) is the received signal from CGM sensor. A brief overview of the basic filters used in noise removal is given below.

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Median Filter : A median filter take the median value of a window of N past glucose values. Y(t) = median ( Yt , Yt-1,..Yt-N+1 ) (3) The advantage of this filter is that it discards the effect of sudden spikes in the signal. FIR and IIR filters : A finite impulse response filter has the form k=a0Yk+a1Yk-1++amYk-m (4) where Y represents the measured glucose value and k is the filtered value which depends on the past m measurements. An Infinite impulse response (IIR) filter has the form k = -a1k-1 a2k-2 - - aNk-N + b0Yk + b1Yk-1++ bmYk-m (5) where the current filtered output is a function of N previously filtered values and m previous measurements. Dexcom16 patented the use of IIR filters for raw signal filtering with N = 3 and m = 3. Medtronic patents show that the raw signals being obtained at 10 second intervals. At the end of each 1 minute intervals the lowest and highest values are removed and the remaining four are averaged to obtain the 1 minute average.[10] From the patent of Steil and Rebrin,[11] it is found that the filters can also be applied to the derivative of the glucose data which is useful as a part of closed loop algorithm based on the rate of change of glucose. Kuure-Kinse et al., applied a dual rate Kalman filter for continuous glucose monitoring[12]. The optimal estimation theory of Knobbe and Buckingham [13]showed that the use of extended Kalman filter accounts for both sensor noise and calibration errors. Fachinetti et al., used the Kalman filtering with individualized error covariances.[14] Facchinetti et al., discussed various aspects in modeling the errors in CGM sensor data[15] and enhanced the accuracy through extended Kalman filteing.[16] Commonly used filters are median filter and moving average filter. The present days filtering algorithms are not adaptive to all intensities of noise. As per the patent [17] it is found that moving average filter is being used in Medtronic CGM systems. Since the signal to noise ratio varies with time, sensor and user, the filtering algorithm should intelligently adapt to inter patient and intra patient variability. Wiener filter and Kalman filter are the choices for adaptive filtering. Wiener filter requires the process to be stationary. Kalman filter will do better for the time varying CGM signal. For reliable real time monitoring and control of glucose, the filtering algorithm should account for (i) Short term errors ( or noise) due to motion artifacts. (ii) Long term errors due to performance deterioration of sensor, Bio fouling, Inflammatory complications etc.. (iii) Uncertainty in physiological parameters. (iv) Filtering of short term errors for the linear case is simple. To account the second criteria, we go for non linear modeling which could be achieved with Extended Kalman filter. But to satisfy the third criteria some artificial intelligence modeling technique is needed. An artificial neural network which does the information processing as per the way of biological neurons would be the best choice. A feed forward neural network with back propagation algorithm would track the physiological variations in CGM signal. In this paper, we propose a Hybrid Filtering Technique (HFT) which comprises a feed forward neural network whose weights are estimated by Extended Kalman Filter (EKF) for denoising of CGM sensor data.

3. Research Method
Glucosim is a web based Diabetes Educator that can be used for the study of Glucose Insulin Interaction in human. This simulator has been developed by the research team of Illinois institute of

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Technology[18] based on the pharmacokinetic model of Pucket [19]. It comprises compartmental analysis of glucose and Insulin in Heart, Brain, Liver, Pancreas, Gastro intestinal tract, Kidney, periphery and subcutaneous tissue etcThe input parameters of Glucosim are age, weight, exercise duration, amount and timing of food intake in calories and insulin applied in units. For the given set of inputs the simulator will give the glucose kinetics in blood, liver, intestine and total glucose uptake. The datasets of blood glucose time series were simulated by setting various values to input parameters in heuristic approach. Time lag is introduced in these glucose profiles to imitate the sensor performance.[20] The sensor signal acts as the reference data signal. The analysis of noise in CGM signal shows that the sensor errors are highly interdependent. However, the exact distribution of CGM noise profiles has not been reported in the literature to date. Specifically no study has reported a histogram of CGM error of values versus gold standard measures.[21] However, an approximate model can be created using available literature and data.. The noisy CGM time series have been generated by adding the appropriate noise distributions with the reference signal. The HFT method is tested first with White Gaussian noise (WGN) and then with combination of WGN and Double exponential noise (also called as Double Laplace distribution). The Laplace distribution is a distribution of differences between two independent variates with identical exponential distribution. The distribution is given by f((x) / ,b) = (1/ 2b) exp (- ( |x-| / b) ) (6) where is a location parameter and b is a scale parameter. The double Laplace Distribution noise is generated separately with two different pairs of standard deviation and mean. This model would help to imitate the sudden peaks and nadirs in CGM time series. The HFT method is assessed with Monte Carlo simulation which allows appropriate performance statistics to be generated. The RMSE between the filtered signal and the reference signal are calculated. Figure 2 gives the overview of the methodology of the work.
Figure 2: Overview of the work
WGN, Double Laplace Noise Glucose Profile from Glucosim

Sensor Data

Noisy CGM

HFT Filter

Filtered CGM

Figure 3 shows a representative noise free glucose profile. The noisy CGM profile with WGN and double Laplace noise distributions are illustrated in figure 4. The noisy CGM profile is applied to HFT. The filtering process is carried out in two phases. First is the training phase and the second is the testing phase. The first 10% of each glucose time series is used to train the neural network, shown in figure 5. During this training phase, weights and bias of the neural nodes are estimated by EKF algorithm. The network is trained to meet the performance criteria of Root Mean Square Error (RMSE) between the actual value and filtered value to be less than 10mg/dL. Updation of weights and biases, enables the network to capture the non linearities in the CGM time series. Once the network is trained, the HFT is ready for testing phase. The remaining 90% of the data series can be sent for filtering.

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Figure 3: Noise free CGM time series

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Figure 4: CGM signal with WGN and Double Laplace Noise
CGM Signal with WGN & Double Laplace Noise 200 180 160

Noise Free CGM Signal 160 140 120 Glucose Values in mg/dL 100 80 60 40 20 0
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Figure 5: Noisy CGM signal with Training and Testing Data Sequences
CGM Signal with WGN & Double Laplace Noise 200 180 160 140 120 100 80 60 40 20 0

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4. Hybrid Filtering Technique

4.1. Neural Network
The architecture of HFT filter is shown in figure 6. It is a multi layer feed forward back propagation neural network with an input, hidden and an output layer. The output and hidden units have bias. The input layer is connected to hidden layer and hidden layer is connected to output layer through interconnection weights. These weights are to be decided by extended Kalman filter algorithm described below. The non linearity in the glucose time series can very well be estimated and corrected by EKF. The EKF provides minimum variance estimates in system applications where the dynamic process and measurement models contain non linear relationships. Since the HFT comprises of only one hidden layer the computational complexity is less in this network.
Figure 6: HFT Neural Network.

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Training Algorithm The training of back propagation network involves four stages, viz 1. Initialization of weights. 2. Feed forward. 3. Back propagation of errors. 4. Updation of weights and biases. During first stage which is the initialization of weights, some small random values are assigned. During feed forward stage each input unit (Xi) receives an input signal and transmits this signal to each of the hidden units Z1,Z2,..Zp. Each hidden unit then calculates the activation function(Bi) and sends its signal Zi to each output unit. The output unit calculates the activation function(Bj) to form the response of the net for the given input pattern.[22] During the back propagation of errors, each output unit compares its computed activation Yk with its target value tk to determine the error. Based on the error, the factor k (k = 1,2,.m) is computed and used to distribute the error at the output unit Yk back to all units in the hidden layer. Similarly the factor j is computed for each hidden unit Zj. For efficient operation of back propagation network, appropriate parameters should be assigned for training.[23] 4.2. Extended Kalman Filter
The minimum variance estimate of state vector of a dynamic discrete time process is governed by a non linear stochastic difference equation X(k+1) = f( X(k),w(k) ) (7) With a measurement vector, Y(k) = h( X(k),v(k) ) (8) Where f and h are non linear vectorial functions.[24] Wk and Vk are the vectors of process and measurement noises respectively. w(k) and v(k) are assumed to be zero mean white noise processes with covariance matrices Qk and Rk respectively. f is the non linear function that relates the state at previous time step k-1 to the state at time step k. h is the non linear function that relates the state and measurement vector. Estimation of state vector X is done similar to linear case. The time update equations are given as follows. Estimate of state vector : x (k + 1 / k) = f ( x (k / k), 0) (9) Estimate of Covariance matrix at kth sampling time : P(k+1/k) = Ak P(k/k) AkT + Wk Qk WkT. The measurement update equations are : Kk = P( k+1/k)HkT( Hk P(k+1/k) HkT + Vk Rk VkT ) -1 x (k + 1/k + 1 ) = x (k + 1 /k) + k (y(k + 1) h( x (k + 1/k),0)) (10) (11) (12)

P (k + 1/ k + 1) = ( I KkHk ) P (k + 1/ k , 0) (13) Where Ak and Hk are the Jacobian matrices of the partial derivatives of f and h with respect to X, whereas Wk and Vk are the Jacobian matrices of partial derivatives of f and h with respect to wk and vk respectively. Kk is the Kalman gain matrix at the kth sample and I is the identity matrix with size as that of X.

5. Experiment
The proposed mechanism was implemented in the working platform of MATLAB (R2010a) to denoise the CGM data. The proposed method has been evaluated with the data from GLUCOSIM simulator. The data has been generated based on the time of meal, CHO(Carbohydrate content) in meal, body

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weight and duration of the simulation. A sample of input parameters is given in table 1. And one of the generated data set with their parameters considered is shown below in table 2.
Table 1: Sample of Parameters for Simulation
Break fast 08:30 1000 Snack 12:00 100 Lunch 13:30 500 75 24 Snack 18:00 500 Dinner 20:00 500 Snack 22:00 200

Time (hh:mm) CHO (mg/kg body weight) Body Weight (kg) Duration of simulation (hour)

The continuous glucose time series data were generated in varied ranges with ages between 10 to 75 and weight between 30 to 87 kg. The calories intake and insulin dosages are chosen in such a way to have hypo and hyper glycemic occurances. 25 data sets were obtained through the simulator. Each in turn were simulated n=20 times with Monte Carlo method. Thus, there are 25x20 = 500 CGM time series in total where each is different due to the addition of noise with random parameters. The noise sequences with variance values in the span of 10 to 200 mg2/dL2, and different scaling and location parameters are applied to the reference glucose profiles. The time lag for the glucose to traverse from blood to interstitial fluid is taken to be average of 6 minutes. [20]
Table 2: Sample of generated dataset through GLUCOSIM
Intestinal Glucose Absorbtion (mg/kg min) 0 0.00543 0.03773 0.10154 0.19601 0.31488 0.43591 0.55367 0.66822 0.77965 0.88801 0.99338 1.09582 1.19539 1.29216 Total Glucose Uptake (mg/kg min) 3.0328 3.0409 3.0422 3.0414 3.0404 3.0406 3.0431 3.0471 3.053 3.0612 3.0775 3.0912 3.1035 3.1321 3.1484 Liver Glucose Production (mg/kg min) 1.58349 1.58155 1.58023 1.57925 1.5785 1.57792 1.57753 1.5773 1.57713 1.57701 1.57688 1.57683 1.5768 1.57676 1.57675

Blood Glucose (mg/dl) 87 86.0751 84.4065 82.7931 81.2454 79.8082 78.5114 77.3589 76.3445 75.4617 74.7045 74.0663 73.5409 73.1222 72.8038

Blood Insulin (mU/ml) 15 15.4191 14.6978 13.9248 13.2024 12.5420 11.9411 11.3950 10.8986 10.4476 10.0377 9.66527 9.3268 9.01922 8.73972

Stomach Glucose (mg/kg) 0 124.7325 373.1423 619.9696 865.2089 984.1856 977.9089 971.6837 965.4982 959.3521 953.2451 947.1770 941.1475 935.1564 929.2034

With the aid of the simulator generated data set, our proposed work HFT filter comprising of neural network and extended Kalman filter has been evaluated with Monte Carlo method and validated with Root Mean Square Error (RMSE). The process and measurement noise variance are initialized with q= 0.1 and r = 0.1 mg2/dL2 respectively. Inputs to the neural network are applied as vectors of size 6 x 1. The state vector is of size 6 x 6. The IG values from the sensor are given to the networks input layer. At hidden layer neural nodes, the weighted inputs are applied with tansigmoidal function. This function introduces a non linearity in the model. The nodes at output layer are applied with linear activation function. The output of the network depends upon the weights Wni,j of the neurons that are determined by the EKF state estimation and correction approach. n represents nth layer and the suffices i,j denotes the traversal of input from ith node in first layer to jth node in next layer. i = 1,2.Ni and j = 1,2,.Nj.

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5.1. Results and Discussion

The noisy CGM signals are applied to the Hybrid Filtering Technique method. The resultant output is compared with the actual noise free CGM time series. RMSE is calculated as the performance metric. The proposed HFT mechanism has been compared with the Moving average filter with exponential weights and the Kalman filter to quantify the capability of HFT in denoising the combined effects of random noise and double Laplace noise. With the trials conducted with 500 simulated data sets, it is observed that the RMSE is minimum in HFT method compared with the other two. The experiments were conducted with different scenarios and some representative results are listed in table 3. The results clearly prove that the HFT mechanism is able to capture and remove the combined noise effects in a superior way than the other methods. This shows that the artificial neural network in HFT is trained well with physiological variations of each individual and it tracks the glucose profile perfectly neglecting the various noise effects in the CGM. The HFT filtered output signal from the noisy version is shown in figure 7.
Figure 7: Denoised CGM signal from HFT filter
Output of HFT filter 200 180 160 G c s V lu sinm/d lu o e a e g L 140 120 100 80 60 40 20 0 Noisy CGM HFT Output

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The correlation coefficient between the HFT filtered signals and the respective reference signals are calculated, which gives a mean of 0.935.
Table 3: Performance Comparison of HFT Filter with Moving Average Filter(MA) and Kalman Filter(K)
Root Mean Square Error ( mg/dL ) Double Laplace Noise MA HFT K Filter Filter Filter 6.2 4.1 3.5 6.1 4.5 3.9 5.9 4.4 4.1 5.3 4.9 3.8 6.3 5.1 4.3 6.8 4.5 2.1 7.7 3.9 2.2 8.1 4.7 2.0 6.1 6.5 2.6 5.5 4.8 4.3 5.9 5.3 4.1 6.6 4.7 3.4 7.0 5.0 2.9 6.6 4.4 2.1 5.5 3.9 2.3

Data Set ID 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

White Gaussian Noise MA HFT K Filter Filter Filter 5.5 4.5 2.3 6.3 5.3 2.5 5.2 4.3 3.2 4.9 4.5 3.6 5.9 5.1 4.1 6.2 5.7 1.3 7.3 6.3 1.6 7.8 6.2 1.8 4.5 6.0 2.0 4.3 5.8 3.5 5.1 4.8 3.1 6.2 5.9 2.5 7.3 6.3 2.0 7.8 6.5 1.7 8.1 7.0 1.5

Combined Noise MA Filter 14.5 9.5 8.1 7.7 6.8 8.3 6.9 9.1 9.4 8.8 10.7 12.0 12.6 11.5 10.3 K Filter 12.0 7.5 6.3 6.1 5.4 6.7 5.8 7.5 7.7 6.5 8.0 10.3 10.5 10.2 5.6 HFT Filter 2.9 4.1 3.5 3.9 4.7 3.8 3.9 4.2 3.3 2.6 2.1 3.1 2.7 2.6 2.5

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6. Concluding Remarks
The Continuous Glucose Monitoring is very much essential for prevention of Diabetic complications. Perfect filtering of various types of noise signals in CGM data enables it to be used for further processing like Hypo/Hyper glycemic alert generation and control input to closed loop artificial pancreas. Conventional filtering methods are not sufficient to track the variations of physiological signal neglecting the noise effects. Our proposed work comprising the intelligent artificial neural network with extended Kalman filter algorithm has proved its success in denoising the CGM signal with simulated data sets. Further research effort is needed for real time implementation.

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