J Appl Physiol 96: 1045–1054, 2004. First published November 14, 2003; 10.1152/japplphysiol.00788.2003. V̇O2, V̇CO2, and RQ in a respiratory chamber: accurate estimation based on a new mathematical model using the Kalman-Bucy method L. Granato,1 A. Brandes,1 C. Bruni,1 A. V. Greco,2 and G. Mingrone2 1 Dipartimento di Informatica e Sistemistica “Antonio Ruberti,” Facoltà di Ingegneria, Università di Roma “La Sapienza,” 00184 Rome; and 2Istituto di Medicina Interna, Università Cattolica del Sacro Cuore, 00168 Rome, Italy Submitted 28 July 2003; accepted in final form 31 October 2003 ACCURATE MONITORING OF GAS exchange [O2 consumption (V̇O2) and CO2 production (V̇CO2)] of a subject in health and disease is of large interest in medical research (4, 9, 17, 20–22). It enables the assessment of important physiological indexes, such as oxidation rate of energy substrate and energy expenditure (6, 7, 12). Although various instruments for indirect calorimetry exist, the respiratory chamber is the only one permitting continuous long-term monitoring (24 h) of patients, thus offering a unique opportunity to study important aspects of energy metabolism in humans practicing their daily life activities (sleeping, eating, physical activity, etc.). The precision of the measurements of respiratory gas becomes of crucial importance to obtain precise metabolic data, as for example, computation of respiratory quotient (RQ) (V̇CO2-to-V̇O2 ratio), which is very sensible to the accuracy of the V̇O2 estimates. To estimate V̇O2 and V̇CO2, conventional methods divide the observation period into small subintervals. For each such subinterval, the following three steps are executed (1, 2, 5, 10–13, 16, 18): measurement phase, in which a series of measurements is collected at any generic subinterval; prefiltering phase, in which the accuracy of the measurements is improved by applying suitable filtering methods (arithmetic mean, cubic splines); and finally, computation phase, in which the prefiltered data are related to the problem unknowns (V̇O2 and V̇CO2) by a mass balance equation that is simply inverted to produce estimates of the unknown values. Some differences do exist between the standard methods regarding mainly the formulation of the mass balance equation, rising from different simplifying hypotheses used. Estimates performed as indicated above are affected by several error sources: 1) measurements are always corrupted by noise and, although prefiltering is applied, considerable residual error remains; 2) the used mass balance equation is only an approximate representation of reality due to the simplifying hypotheses used; 3) V̇CO2 and V̇O2 are obtained by simple inversion of the mass balance equation, without applying any mechanism to limit the propagation of the errors introduced by 1 and 2. The above error sources are always present in a real experimental setting and cannot be completely eliminated; therefore, it is of high importance to apply procedures and methods to minimize such negative effects. The main goal of the present study is to propose adequate procedures to obtain more accurate and reliable estimates of the variables of interest (V̇O2, V̇CO2, and, moreover, RQ). Furthermore, it is of interest to validate the proposed method with respect to conventional ones. To do so, the following points were studied: 1) introduction of adequate stochastic model to describe the dynamics of gas exchange in a respiratory chamber and of the measurement processes; 2) analysis of the proposed model and identification of the statistical parameters of the stochastic processes involved; 3) use of the wellknown Kalman-Bucy (KB) estimation method to realize online filtering and offline interpolation, thus producing accurate estimates of V̇O2 and V̇CO2; 4) experimental validation of the proposed model and of the estimation procedure by processing the data obtained by simulated (known injected gas rates) and real (humans) gas exchange in the respiratory chamber. Furthermore, the results obtained by using the proposed method Address for reprint requests and other correspondence: G. Mingrone, Istituto di Medicina Interna, Universita Cattolica del Sacro Cuore, 00168 Rome, Italy (E-mail: [email protected]). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. indirect calorimetry; respiratory gas exchange; energy expenditure; Kalman filter; stochastic model http://www.jap.org 8750-7587/04 $5.00 Copyright © 2004 the American Physiological Society 1045 Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 Granato, L., A. Brandes, C. Bruni, A. V. Greco, and G. Mingrone. V̇O2, V̇CO2, and RQ in a respiratory chamber: accurate estimation based on a new mathematical model using the KalmanBucy method. J Appl Physiol 96: 1045–1054, 2004. First published November 14, 2003; 10.1152/japplphysiol.00788.2003.—A respiratory chamber is used for monitoring O2 consumption (V̇O2), CO2 production (V̇CO2), and respiratory quotient (RQ) in humans, enabling long term (24-h) observation under free-living conditions. Computation of V̇O2 and V̇CO2 is currently done by inversion of a mass balance equation, with no consideration of measurement errors and other uncertainties. To improve the accuracy of the results, a new mathematical model is suggested in the present study explicitly accounting for the presence of such uncertainties and error sources and enabling the use of optimal filtering methods. Experiments have been realized, injecting known gas quantities and estimating them using the proposed mathematical model and the Kalman-Bucy (KB) estimation method. The estimates obtained reproduce the known production rates much better than standard methods; in particular, the mean error when fitting the known production rates is 15.6 ⫾ 0.9 vs. 186 ⫾ 36 ml/min obtained using a conventional method. Experiments with 11 humans were carried out as well, where V̇O2 and V̇CO2 were estimated. The variance of the estimation errors, produced by the KB method, appears relatively small and rapidly convergent. Spectral analysis is performed to assess the residual noise content in the estimates, revealing large improvement: 2.9 ⫾ 0.8 vs. 3,440 ⫾ 824 (ml/min)2 and 1.8 ⫾ 0.5 vs. 2,057 ⫾ 532 (ml/min)2, respectively, for V̇O2 and V̇CO2 estimates. Consequently, the accuracy of the computed RQ is also highly improved (0.3 ⫻ 10⫺4 vs. 800 ⫻ 10⫺4). The presented study demonstrates the validity of the proposed model and the improvement in the results when using a KB estimation method to resolve it. 1046 V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD Fig. 1. Simplified presentation of gas exchange in the respiratory chamber. i(t), Flow rate of input fresh air at time t; o(t), flow rate of output stale air at time t; ug(t), gas production rate (positive or negative) at time t; V, volume. are compared with the ones obtained by applying a conventional method (18). METHODS J Appl Physiol • VOL V䡠 d g 关c 共t兲兴 ⫽ i共t兲 䡠 cgi 共t兲 ⫺ o共t兲 䡠 cog共t兲 ⫹ ug共t兲 dt (1) where V is volume, and the gas volumes and flows are expressed in conditions. The following simplifying hypotheses are now assumed. 1) The existence of an adequate ventilation system in the respiratory chamber allows us to assume that “a rapid mixing of respiratory gas with air occurs in the chamber” (explicit in Ref. 16 and implicit in all others); therefore STP c og共t兲 ⫽ cg共t兲 (2) 2) The concentration of the g in the i is constant, with a value determined by its standard volumetric fraction in atmospheric air c gi 共t兲 ⫽ c g (3) 3) The i is equal to the o and is perfectly measured by an adequate sensor i共t兲 ⫽ o共t兲 ⫽ 共t兲 (4) Defining now the difference in the volumetric fractions of the gas considered c̃ g共t兲 ⫽ cog共t兲 ⫺ c g (5) and substituting Eqs. 2–5 in Eq. 1 results in the following linear differential equation d g 共t兲 g 1 关c̃ 共t兲兴 ⫽ ⫺ 䡠 c̃ 共t兲 ⫹ 䡠 ug共t兲 dt V V (6) Unfortunately, in real life, the hypotheses of Eqs. 2–4 are never perfectly fulfilled, and, as a consequence, the right side of Eq. 6 is not Table 1. Anthropometric characteristics of subjects Subject No. Age, yr Gender Height, m Weight, kg BMI, kg/m2 1 2 3 4 5 6 7 8 9 10 11 46 38 51 30 26 43 42 55 52 59 47 F M F F M F F F M F M 1.52 1.78 1.61 1.75 1.62 1.55 1.56 1.50 1.76 1.63 1.83 95 145 123 119 116 96 112 90 132 63 130 41.1 45.8 47.5 38.9 44.2 40.0 46.0 40.0 42.6 23.7 38.8 F, female; M, male; BMI, body mass index. 96 • MARCH 2004 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 The respiratory chamber. The respiratory chamber, built in the Metabolism Unit, Catholic University, School of Medicine, Rome, Italy, has a volume of 23.62 m3. It exchanges gas volumes with the external environment [input flow i (l/min); output flow o (l/min)] through two sole apertures by means of an adequate pump, mounted to the output aperture, creating a regular airflow. This o is measured by a flowmeter generating an analog voltage output (0–10 V), directly proportional to the measured airflow (0–150 l/min). A certain portion (⬃1 l/min) is directed to two gas analyzers (specified below), producing the fractions of oxygen and carbon dioxide in the sampled airflow. The carbon dioxide concentration is measured by a 2% full scale (0–2%) infrared absorption analyzer (URAS 3G, Hartmann & Braun, Frankfurt, Germany), generating voltage output (2–10 V) directly proportional to the measured fraction (0–2%). The oxygen concentration is assessed by a 2% full scale (19–21%) paramagnetic analyzer (Magnos 4G, Hartmann & Braun), generating an analog voltage output (2–10 V) directly proportional to the measured fraction (19– 21%). Both gas analyzers are operating with a precision of 0.02 volumetric percentages. The zero values of both analyzers were calibrated by allowing fresh air to flow through the sample and the reference lines simultaneously, whereas the span values were calibrated using commercially available gas mixtures (Rivoira, Torino, Italy). The composition of the gas mixture used to calibrate the O2 analyzer was 19.48% O2-balance N2. The composition of the gas mixture used to calibrate the CO2 analyzer was 1.5% CO2-balance N2. The calibration procedure is as specified by the manufacturers of the gas analyzer and was carried out at the beginning of each experimental session. The three voltage signals (airflow, O2 fraction, and CO2 fraction) are sampled by a data-acquisition board (Keithley DAS-1601), mounted on a standard desktop. An adequate software realizes the necessary procedures to compute and memorize the sampled measurements at a preset sampling period. The memorized data is then used to compute the V̇O2 and the V̇CO2 of the subjects in the respiratory chamber, using either the proposed method or the method reported in Ref. 18, which is a representative example of most conventional methods presented in the literature. A dynamic model for the gas exchange in the respiratory chamber. The scope of this section is to derive a general simple mathematical model to describe the following phenomenon: a controlled volume is subject to an i, an o, and within it a source produces or consumes a gas g (see Fig. 1). This model is later used to describe both V̇CO2 and V̇O2 by a subject in the respiratory chamber. The following notation is introduced: cg(t), the mean volumetric spatial fraction of g at time t; i(t), flow rate of input fresh air at t (in l/min); cgi (t), volumetric fraction of g at the i at t; cgo(t), volumetric fraction of g at the o at t; o(t), flow rate of output stale air at t (in l/min); ug(t), gas production rate (positive or negative) at t (in l/min); and [0,T], the time interval describing the duration of the experiment, where t represents a time instant within this interval. With the above notation, the mass conservation principle allows the writing of the following fundamental equation 1047 V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD Fig. 2. Mean fitting error vs. different values of the variance pair (modeling error variance 2 m , variance related with random walk model 2u). d g 共t兲 g 1 关c̃ 共t兲兴 ⫽ ⫺ 䡠 c̃ 共t兲 ⫹ 䡠 ug共t兲 ⫹ wm共t兲 dt V V (7) where wm describes the cumulative effect of all approximations introduced by the simplifying hypotheses above (inhomogenity of gas mixture, variation of standard gas fractions, variation of airflows, etc.). The value of this error at each time instant t is not known; nevertheless, it can be well described by a stochastic variable, characterized by its statistical properties (expected value, variance, etc.). Equation 7 turns out to be a Stochastic Linear Differential Model of the phenomenon. A fundamental hypothesis that lies in the basis of this work is that the wm can be accurately described as a zero mean white Gaussian stationary random process. Such a process is com2 pletely defined by its variance, denoted by m . Next, a dynamic description of the gas production/consumption rate ug is proposed. A generic gas source having a constant production rate can be described by the simple model d/dt [ug(t)] ⫽ 0. If, on the other hand, the production rate varies in an unknown manner around a nominal value, the following simple stochastic model can be used d g 关u 共t兲兴 ⫽ wu共t兲 dt To complete the mathematical modeling of gas exchange in the respiratory chamber, the measurement process has to be formulated as well. The available measurements are the differences in the volumetric fractions of the gas considered, as defined in Eq. 5, and are affected by an additive measurement noise (present in any real experimental setting) y共t兲 ⫽ c̃ g共t兲 ⫹ 共t兲 where is a white Gaussian process, fully identified by its expected value and variance 2. Equation 9 is widely referred to as the measurement equation. Putting together Eqs. 7–9, the complete model describing a typical experimental setting of the respiratory chamber can be obtained in a compact matrix form 再 d 关x共t兲兴 ⫽ A共t兲 䡠 x共t兲 ⫹ w共t兲 dt y共t兲 ⫽ C 䡠 x共t兲 ⫹ 共t兲 where x共t兲 ⫽ 冋 册 J Appl Physiol • VOL 冋 册 冋 册 共t兲 1 c̃ g共t兲 wm共t兲 ⫺ , A共t兲 ⫽ , C ⫽ 关1 V V , w共t兲 ⫽ g u 共t兲 wu共t兲 0 0 (8) where wu is a zero-mean white Gaussian random process, describing the variations in the production rate, i.e., the error in assuming a constant production/consumption rate. This random process is completely defined by its variance 2u. The model in Eq. 8 is commonly referred to as random walk and, in this case, plays only a descriptive role and should not be interpreted as a model of the physiological phenomenon of the gas production. Because V̇O2 and V̇CO2 are highly related processes, it is reasonable to assume similar temporal behavior (dynamic model), which implies the use of the same 2u. The results obtained, presented in the sequel, further validate the use of this simple stochastic model and the parameters here defined. (9) (10) 0兴 (11) The model in Eq. 10 cannot be directly utilized due to the following reasons: 1) measurements are not available on any time instant t, but Table 2. Variance of noise processes Parameter Value Units Evaluation Method 2 m 2u 2 10⫺12 2.5 ⫻ 10⫺3 10⫺8 min⫺2 l2/min4 Optimal fitting of known inputs Optimal fitting of known inputs Measurements of null gas fractions 2 m , modeling error variance; ŷ2u, variance related with random walk model; 2, variance of measurement noise. 96 • MARCH 2004 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 exactly equal to the left side. To account for the latter, it is possible to add a corrective term, wm, denoted modeling error, resulting in 1048 V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD Table 3. Results of the experiments with simulated gas production Experiment A Experiment B Experiment C Mean KB Interpolator KB Filter Standard Method (18) 19⫾1.0 18⫾1.0 10⫾0.7 15.6⫾0.9 42⫾2.7 28⫾2.0 21⫾1.6 30.3⫾2.1 298⫾63.2 127⫾19.8 132⫾24.0 186⫾35.6 Values are means of the absolute values of the fitting error (with respect to the known gas production rate) ⫾ SE and are reported in ml/min. KB, Kalman-Bucy. 再 where H共 j兲 ⫽ 冋 x共 j ⫹ 1兲 ⫽ H共 j兲 䡠 x共 j兲 ⫹ ⌬ 䡠 w共 j兲 y共 j兲 ⫽ C 䡠 x共 j兲 ⫹ 共 j兲 m共 j兲 0 n 1 册 m共 j兲 ⫽ 1 ⫺ ⌬ 䡠 共 j兲 V (12) n ⫽ ⌬/V (13) Identification of model parameters. To complete the exact model formulation, specifying the values of the following parameters is wm m2 0 needed: 1) ⌿w ⫽ cov 共w兲 ⫽ cov ⫽ , denoting the wu 0 u2 2 process noise covariance matrix; 2) ⌿ ⫽ cov () ⫽ , denoting the measurement noise covariance matrix. Note that, because the measurement is a scalar, then is also a scalar, and its covariance matrix reduces simply to the noise variance. The 2 has been experimentally obtained by performing a set of measurements of a known constant volumetric fractions (specifically zero) and calculating the variance of the obtained measurements. 冉 冊 冉 冊 Fig. 3. Estimates of the known input in experiment A. The Kalman-Bucy (KB) interpolator estimates (top), the KB filter estimates (middle), and the estimates computed by a conventional method (bottom) are indicated by thick lines. The reference input is indicated by thin lines. J Appl Physiol • VOL 96 • MARCH 2004 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 only at certain discrete time instants tj ⫽ j䡠⌬, j ⫽ 0, 1, . . . , N, where ⌬ is a constant sampling period and N is the number of measurements, N ⫽ T/⌬; 2) the model is to be resolved using computer software, which is by nature a discrete time digital process. To account for the above, the following discrete time model is used in the sequel 2 As far as m and 2u are concerned, the authors have assessed their values by performing the following data fitting procedure. 1) Three experiments were carried out in which gas was injected into the respiratory chamber at accurately measured rates. These gas inputs simulated a step-type phenomenon, starting with zero rates for 20 min and followed by some constant value (200 ml/min in experiment A, 120 ml/min in experiments B and C) during the subsequent 20 min. Gas fractions and airflows were measured with a sampling period of 5 s. 2) The gas production has been estimated by applying the KB 2 methods using different values for m within the interval (10⫺16 . . . 2 ⫺4 ⫺2 10 ) (min ), and for u within the interval (10⫺10 . . . 102) (l2/min4). The 2 was fixed to the value derived experimentally as specified above. 3) The fitting error (mean of the absolute values of the instantaneous errors) when comparing the known gas inputs with their 2 estimates was calculated for each variance pair (m , 2u). 2 4) The selected values for m and 2u are the ones minimizing the fitting error. The KB estimation method. The problem of estimating the state x( j) using the available measurements y( j) in Eq. 12 turns out to be a linear Gaussian problem that can be solved by applying the KB estimation method. This is a well-known estimation procedure, which processes the measured data using rational criteria and accounts for the available a priori information regarding both the deterministic and the stochastic nature of the observed phenomena. The estimated state at time j⌬ based on the set of measurements y(0) . . . y(k⌬) is denoted x̂( jⱍk). The larger the set of measurements, the more accurate becomes the estimate. The KB procedure has an important theoretical property, being the Best Linear Unbiased Estimator, in the sense of minimizing the expected value of the squared estimation error. The estimation error is defined as the difference between the estimated and the true value, i.e., ê( jⱍk) ⫽ x( j) ⫺ x̂( jⱍk). The demonstration of this property is not straightforward; the interested reader is, therefore, referred to various texts, e.g., Refs. 3, 8, 19. In general, the estimation problem can be resolved for the following three possibilities: 1) j ⬎ k, prediction, where the time index of the estimate j is in the future of the available measurements; 2) j ⫽ k, V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD 1049 filtering, where the time index of the estimate is equal to that of the available measurements [this case is used for online (real-time) implementation]; and 3) j ⬍ k, interpolation, where the time index of the estimate j is in the past of the available measurements, thus enabling the use of more information with respect to the other cases. The KB method computes iteratively both the state estimate, x̂( jⱍk), and the covariance matrix of the estimation error ⌿ ê 共 j兩k兲 ⫽ cov 关ê共 j兩k兲兴 (14) Application of the KB methods requires the specification of the covariance matrices describing the random processes used, i.e., ⌿w ⫽ cov (w) and ⌿ ⫽ cov (). Furthermore, it is necessary to specify initial conditions for both the estimated state, x̂( j ⫽ 0), and the ⌿ê, ⌿ê( j ⫽ 0), the choice of which is not critical to the performance of the KB method because it is proved that, as the index j grows, the estimate becomes independent of this selection (8). According to the information available at the initial conditions of the experiments, the following values are used in this study: 1) initial state, for the V̇O2 estimates 0 0 x̂共 j ⫽ 0兲 ⫽ and for the V̇CO2 estimates x̂共 j ⫽ 0兲 ⫽ , 0.3 0.2 where the first component is the initial differential volumetric fraction (unitless) and the second is the initial gas production rate (in l/min); 0.1 0 2) initial ⌿ê, ⌿ê共 j ⫽ 0兲 ⫽ , where 0.1 is the variance 0 1 associated with the gas fraction estimation error, thus dimensionless, and 1 is associated with the ug [therefore, in (l/min)2]. 冉 冊 冉 冊 冉 冊 J Appl Physiol • VOL Various formulations of the above algorithms are known in literature. The APPENDIX reports the formulation realized by the authors (3). In this study, the authors present the implementation of both interpolator (offline) and filter (online) versions of the KB method. Experimental validation. Experimental validation is performed by two sets of experiments. The first set is realized by simulating gas production within the respiratory chamber, at accurately measured rates. Gas mixtures of known composition (20% CO2-1% O2-balance N2) were injected into the respiratory chamber at an accurately measured flow rate. The goals of this procedure were to confirm and validate the ability of the proposed method to reproduce a good estimate of the known gas production. Three such experiments were carried out, starting with zero CO2 injection for 20 min followed by 20 min of a known level of CO2 gas (200 ml/min in experiment A; 120 ml/min in experiment B; 120 ml/min in experiment C), thus creating a step-type phenomenon, to be estimated by the proposed method. Flow and concentration measurements were performed at the frequency of 0.2 Hz. The second set involves humans occupying the respiratory chamber. Eleven subjects (4 men and 7 women) were studied. None had diabetes mellitus or any endocrine disease. Their anthropometric characteristics are reported in Table 1. The nature and purpose of the investigations were explained to all subjects before they agreed to participate in the study, which followed the protocol guidelines of the Institutional Review Board. At the time of the examination, all of the subjects studied were on an “ad libitum” diet with the following 96 • MARCH 2004 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 Fig. 4. O2 consumption (V̇O2) and CO2 production (V̇CO2) of subject 11. Proposed method, solid line; standard method, dotted line. The peak corresponds with the physical exercise. 1050 V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD Fig. 5. Estimated respiratory quotient (RQ) of subject 11 throughout the 24-h experiment. Proposed method, solid line; standard method, dotted line. J Appl Physiol • VOL trum should be concentrated on the lower frequencies and should tend to zero on high frequencies. The existence of high-frequency components in a computed spectrum denotes the presence of estimation errors. To quantify these noisy components, the area contained below the spectrum was calculated, starting from the frequency of 0.05 (min⫺1) (i.e., oscillation periods shorter than 20 min). The resulting area (signal power) is proportional to the power of the noisy content and has the dimension of the signal squared, dimensionless for the RQ case and squared milliliters per minute for the V̇O2 and V̇CO2. Statistics. For the experiments with simulated gas production rate, the results are reported as means of the absolute values of the fitting error ⫾ SE, whereas, for experiments with humans, the results are reported as means ⫾ SE, computed over the 11 subjects. RESULTS Model parameters identification. Statistical properties of are assessed by measurements of null gas fractions in the respiratory chamber, resulting in a zero-mean noise {E[(t)] ⫽ 0} and 2 ⫽ 10⫺18 (unitless). As for ⌿w, Fig. 2 describes the fitting error obtained when the computed estimate is compared to the known gas production rate. Those values are 2 plotted vs. different values of the pair (m , 2u) used in the KB 2 method. The minimizing values are m ⫽ 10⫺12 min⫺2 and 2u ⫽ 2.5 ⫻ 10⫺3 l2/min4. Table 2 summarizes the values of all of the parameters used in the sequel. Experimental validation. Results in terms of mean absolute fitting error with regard to the known inputs are presented in Table 3. Figure 3 shows the results of experiment A. The three subfigures plot the performance of the methods applied: KB interpolator, KB filter, and the conventional method (18). The known value of the gas production rate is plotted by a thin line. Note that KB estimates are available at the measurement 96 • MARCH 2004 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 average composition: 60% carbohydrates, 30% fat, and 10% proteins (at least 1 g protein/kg body wt). This dietary regimen was maintained for 1 wk before the study. The day preceding the experimental session, the patients entered the Energy Metabolism Research Unit in the fasted state. Each subject occupied the respiratory chamber for 24 h, practicing normal activity and also a physical exercise during 30 min, as specified below. Before the experiment, the subjects were allowed to practice walking on the motorized treadmill, until they were able to walk without holding on to the railings, to become familiar with the testing equipment. The physical exercise includes walking for 30 min at 10% grade and with a constant speed of 3 km/h. Flow and concentration measurements were performed at the frequency of 1 Hz and averaged over a 5-min period. As previously stated, conventional methods all compute respiratory volumes by inverting a mass balance equation, similar to the one in Eq. 6. In this study, the estimates performed using the proposed method are compared with the ones obtained by applying the method in Ref. 18, based on the three phases described in the Introduction. Gas fraction measurements are collected over a certain time period (5 min with humans and 1 min for the experiments with simulated gas production) and prefiltered using arithmetical mean. The ug are then computed by solving the equations specified there (Eqs. 3–6 in Ref. 18). Note that, when applying this method, prefiltering by averaging is needed, whereas, when applying the KB methods, no such prefiltering is required, and estimates are available with the same temporal resolution as the measurements. Analysis of the results. Regarding the experiments with simulated gas production rates, it is possible to compare the estimates with this known input and to compute the instantaneous fitting error. The authors have chosen the mean of the absolute value of this fitting error as an index for the quality of the estimates. Concerning humans, the true ug are unavailable for comparison. An alternative comparison approach makes use of the spectra of the estimates. The spectrum of a time series provides information with regard to its temporal behavior. Respiratory gas exchange, as a natural biological phenomenon, has a limited bandwidth; therefore, its spec- V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD DISCUSSION Methods presented in the literature to compute respiratory gas production/consumption of a subject in a respiratory chamber are all based on similar mass balance equations, relating the available observations (measurements of volumetric gas fractions, o) with V̇O2 and V̇CO2 (1, 2, 5, 10, 11–13, 16, 18). Some differences do exist between the standard methods, mainly regarding the formulation of the mass balance equation, rising from the different simplifying hypotheses used. Some authors (2, 18) address the problem of noise attenuation by applying certain prefiltering methods but do not explicitly consider the effects of measurement noise and other uncertainties. Heymsfield et al. (10) have formulated for the first time the problem using the terminology of dynamic systems theory, introducing the concepts of stochastic modeling, explicitly considering measurement noise and process noise, fundamental in real applications. However, no solution to the estimation problem was proposed based on those concepts. In this paper, the authors propose a general stochastic mathematical model describing the dynamics of gas exchange within a controlled volume using an input-state-output approach. The used model is linear, and the stochastic variables describing the uncertainties are considered as zero mean white Gaussian processes, therefore formulating the problem as a Fig. 6. Spectral analysis of the V̇O2 and V̇CO2 estimates. Mean spectra are shown of KB interpolator, KB filter, and standard method, computed over the 11 subjects. The spectra of the KB methods are almost identical. J Appl Physiol • VOL 96 • MARCH 2004 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 sampling period (i.e., every 5 s), whereas the conventional method provides estimates every 60 s, due to the prefiltering performed. As for experiments with humans, typical results of obtained estimates are portrayed in Fig. 4 (V̇O2 and V̇CO2) and in Fig. 5 (RQ). Figure 6 shows the mean power spectral density (computed over the 11 subjects) of the V̇O2 and V̇CO2 estimates. Note that the spectra are almost identical, but at high frequencies the spectra of the KB estimates are clearly lower than the spectrum of the estimate by the standard method and are converging to zero. Figure 7 plots the results obtained by spectral analysis of the RQ estimates. Note that the units of the signal power are the square of the signal units over frequency units. Because the RQ is dimensionless, the resulting spectrum is quoted in minutes, whereas, for the gas rates, the spectra are in units of milliliters squared per minute. The time scale in Figs. 4–7 refers to the experiment duration, where the initial time (instant 0) coincides with 0800. Table 4 presents the high-frequency signal power (i.e., oscillatory components with periods shorter than 20 min) computed as the area of the spectra at high frequencies for the estimates performed by the three methods. These data are proportional to the residual noise content in the estimates. Figure 8 shows the temporal evolution of the ⌿ê as produced iteratively by the KB filter algorithm. 1051 1052 V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD Linear Quadratic Gaussian (LQG) problem. Different from Ref. 10, the ug (V̇O2 and V̇CO2) are treated as part of the system state, and, therefore, their estimation using the classic KB methods is made possible. As it is well known, the KB estimation method is optimal for such problems (LQG) in the sense of minimizing the expected value of the squared estimation error. The accuracy improvement is verified by the experimental validation performed in this study. Optimal fitting of the known simulated gas production rates is achieved by using the model parameters reported in Table 2. 2 The low value of m points out that the modeling errors are negligible, thus implying that the stochastic modeling (Eq. 7) is very adequate for this class of problems (dynamics of gas exchange in a controlled volume) and that the assumed hypotheses are well satisfied. Regarding 2u, its value describes the uncertainty in variations in the temporal evolution of the ug and should be, therefore, large enough to account for abrupt changes, e.g., the ones occurring at the beginning and ending of the physical exercise. One possible modification might be the Table 4. Spectral content at noise (high) frequencies Units RQ V̇O2 (ml/min)2 V̇CO2 (ml/min)2 KB Interpolator KB Filter Standard Method (3.2⫾2.0)⫻10⫺5 2.9⫾0.8 1.8⫾0.5 (6.1⫾2.2)⫻10⫺4 90.8⫾22.5 57.6⫾15.1 (8.1⫾4.0)⫻10⫺2 3,440⫾824 2,057⫾532 Values are means ⫾ SE for 11 subjects. RQ, respiratory quotient; V̇O2, O2 consumption; V̇CO2, CO2 production. J Appl Physiol • VOL use of a time-dependent 2u ⫽ 2u(t), in particular, considering large 2u at the instants of beginning and ending of the physical exercise. Such modification requires the use of a priori information regarding these instants. The experiments with simulated gas production rates are an important procedure to validate both the proposed model and the estimation method, because they offer a unique opportunity to compare the estimates of a variable with its true values. Clearly the results obtained by applying the proposed method are much better than those obtained by using the standard (see Table 3). Note in Fig. 3 the large variations in the standard method, due, in all probability, to the propagation of the measurement and model errors into the computation of the gas production. Contrarily, the KB estimates are much smoother, where KB interpolator performs better than the KB filter, as expected, and removes the delay in detecting the step phenomenon. Moreover, the KB methods are not constrained regarding the time resolution, as it is possible to apply the KB method for any sampling period ⌬. In fact, at the experiments with simulated gas production, the KB methods process the measurements at 5-s intervals, with no averaging (prefiltering) involved, whereas the conventional method (18) demands averaging of the measurements over some significant period (60 s, i.e., 12 samples). The KB methods produce estimates that are more accurate and with higher temporal resolution (5 s in the KB estimates vs. 60 s in the standard method). 96 • MARCH 2004 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 Fig. 7. Spectral analysis of the RQ estimates. Mean spectra over the 11 subjects are shown. V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD 1053 Regarding experiments with humans, the measurement data were available already averaged over a 5-min period (prefiltered). In this case, the obtained results demonstrate that, by using the KB method, it is possible to further improve the estimates and to attenuate residual noise content that is not removed by the prefiltering process. Note in Figs. 4 and 5 that the standard method produces highly scattered estimates, making it hard to deduce the physiological condition of patients, whereas the ones obtained using the proposed methods are much smoother. Moreover, as it is well known, an acceptable range for RQ values is from 0.7 to 1.0. Clearly the estimates by the standard method fail to comply with this range, whereas the KB estimates generally meet this constraint. The spectral analysis demonstrates that, at low frequencies, all spectra (by the different methods) are practically identical. Nevertheless, Fig. 6 clearly shows that the spectra of the standard method estimates do not go to zero on high frequencies (thus denoting high-noise content), whereas the spectra of the KB estimates do converge to zero on those frequencies. A similar and even more distinguished phenomenon is revealed J Appl Physiol • VOL by the spectra of the RQ in Fig. 7. Table 4 quantifies the noise contents, clearly visible in Figs. 6 and 7. The noise content in the estimates obtained by the standard method is two to three orders of magnitude larger than that obtained by the KB methods, thus confirming the superiority of the proposed method in the case of human patients as well. Although variations between different subjects are sometimes large, the superiority of the KB methods over the conventional method is, again, very clear. Figure 8 plots the temporal evolution of the diagonal elements of the ⌿ê (Eq. A6). These values are, in fact, online estimates of the accuracy of the estimation procedure. Note that this variance converges rapidly to a steady-state value, thus confirming the filter stability and its robustness with regard to the initial condition values. This fact indicates quasistationary behavior of the filter, resulting from the fact that the temporal variations in the matrix H(j) (Eq. 13) are negligible. In such case, it might be possible to use the steady-state version of the KB algorithm (the Wiener filter) and reduce the computational load, although in this study it was preferred to use the more general method. 96 • MARCH 2004 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017 Fig. 8. Temporal behavior of the estimation error covariance matrix, computed by the KB filter. 1054 V̇O2 AND V̇CO2 ESTIMATES VIA KALMAN-BUCY METHOD In conclusion, a general mathematical model is presented, accurately describing gas exchange in a respiratory chamber. This model serves to estimate V̇O2 and V̇CO2 by applying the KB methods, resulting in estimates highly superior to the ones obtained by conventional method in all cases studied. Computation of RQ, based on the obtained estimates, complies better with biological understanding of such phenomenon. APPENDIX: KB FILTER FORMULATION Following the presentation in Ref. 3, the general LQG estimation problem can be solved by three sequential phases: 1) single-step prediction, 2) filtering, and 3) interpolation. Single-step prediction. F共 j兲 ⫽ H共 j兲 䡠 ⌿ ê 䡠 共 j兩 j ⫺ 1兲 䡠 C T 䡠 关C 䡠 ⌿ê 䡠 共 j兩 j ⫺ 1兲 䡠 CT ⫹ ⌿兴⫺1 (A1) G共 j兲 ⫽ H共 j兲 ⫺ F共 j兲 䡠 C (A2) 2 ⫹ F共 j兲 䡠 ⌿ 䡠 FT共 j兲 x̂共 j ⫹ 1兩 j兲 ⫽ G共 j兲 䡠 x̂共 j兩 j ⫺ 1兲 ⫹ F共 j兲 䡠 y共 j兲 (A3) (A4) With the use of initial conditions for the state x̂( j ⫽ 0) and the initial error covariance matrix, ⌿ê( j ⫽ 0), as provided in METHODS. Filtering. x̂共 j兩 j兲 ⫽ H ⫺1 共 j兲 䡠 x̂共 j ⫹ 1兩 j兲 ⫺1 ⌿ ê 䡠 共 j兩 j兲 ⫽ H 共 j兲 䡠 ⌿ ê 䡠 共 j ⫹ 1兩 j兲 䡠 H ⫺1 T (A5) 共 j兲 ⫺ ⌬ 䡠 H⫺1共 j兲 䡠 ⌿w 䡠 H⫺1 共 j兲 T 2 (A6) Smoothing. 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