Forward-backward Approach Research Articles

Etrolizumab Population Pharmacokinetics (Pop PK) and Covariate Analysis in Patients With Moderately to Severely Active Ulcerative Colitis (UC)

Introduction: Etrolizumab is a humanized IgG1 monoclonal antibody that specifically binds the β7 subunit of α4β7 and αEβ7 integrins. Clinical activity of etrolizumab has been observed in patients with moderate-to-severe UC in a phase 2 trial. The objective of this Pop PK analysis was to characterize covariate effects on the PK profile of etrolizumab. Methods: This analysis included data from 145 etrolizumab-treated patients from 3 studies: a phase 1 dose-escalation study (single doses at 0.3, 1, 3 or 10 mg/kg intravenously [IV] or 3 mg/kg subcutaneously [SC] or 3 monthly doses at 0.5, 1.5 or 3 mg/kg SC or 4 mg/kg IV), a phase 2 efficacy and safety study (2 SC dose cohorts of 100 mg at weeks 0, 4 and 8 or 420 mg at week 0 followed by 300 mg at weeks 2, 4 and 8) and a phase 2 open-label extension study (300 mg SC monthly). A stepwise forward addition and backward elimination approach was used to evaluate the impact of the following baseline covariates on etrolizumab PK: age, sex, body weight (BW), Mayo Clinic score, albumin, C-reactive protein, fecal calprotectin, prior use and response to anti-tumor necrosis factor α biologics and concomitant treatment with steroids or immunosuppressants. The Pop PK analysis was performed using NONMEM 7.1.2. Results: A 2-compartmental model with first-order absorption and elimination kinetics described etrolizumab PK well. BW and baseline serum albumin were identified as significant covariates for clearance (CL) (p<0.001); each explained 16% and 30% of the interindividual variability (IIV) of CL, respectively. Simulation showed similar exposure variability for a BW-based-dose or a fixed-dose. No other covariates were found to have significant impact on etrolizumab PK. The final model estimated the typical population CL value and central volume of distribution to be 0.245 L/day and 3.2 L, respectively. The elimination half-life and SC bioavailability were estimated to be 11 days and 53%, respectively. The IIV of evaluated PK parameters ranged from 19% to 67%. Pop PK simulation estimated that 100 mg nominal dose (105 mg actual dose) every 4 weeks, the proposed phase 3 dose regimen, can maintain a steady-state trough concentration of >1.7 μg/mL in 85% of patients (1.7 μg/mL is the observed minimum drug level associated with full β7 receptor occupancy in peripheral blood and colonic tissue). Conclusion: Etrolizumab exhibited linear PK at the target therapeutic dose. Based on the available data, BW and baseline serum albumin were identified as statistically significant covariates for CL. However, given the favorable safety and efficacy profiles for etrolizumab, the impact of these covariates on the therapeutic outcome is expected to be minimal and not clinically relevant. Disclosure - Xiaohui (Tracey) Wei, Diana Luca, Yehong Wang, Sharon O’Byrne, Rich Erickson, John D. Davis and Meina T. Tang are employees of Genentech, Inc.

Missing Data Restoration Algorithm

The paper presents a novel algorithm for restoration of the missing samples in additive Gaussian noise based on the forward–backward autoregressive (AR) parameter estimation approach and the extrapolation technique. The proposed algorithm is implemented in two consecutive steps. In the first step, the forward–backward approach is used to estimate the parameters of the given neighbouring segments, while in the second step the extrapolation technique for the segments is applied to restore the samples of the missing segment. The experimental results demonstrate that the restoration error of the samples of the missing segment using the proposed algorithm is reduced as compared with the Burg algorithm.

A reduced-complexity scheme using message passing for location tracking

Abstract This article presents a low-complexity and high-accuracy algorithm using message-passing approach to reduce the computational load of the traditional tracking algorithm for location estimation. In the proposed tracking scheme, a state space model for the location-estimation problem can be divided into many mutual-interaction local constraints based on the inherent message-passing features of factor graphs. During each iteration cycle, the message with reliability information is passed efficiently with an adaptive weighted technique and the error propagation law, and then the message-passing approach based on prediction-correction recursion is to simplify the implementation of the Bayesian filtering approach for location-estimation and tracking systems. As compared with a traditional tracking scheme based on Kalman filtering (KF) algorithms derived from Bayesian dynamic model, the analytic result and the numerical simulations show that the proposed forward and one-step backward tracking approach not only can achieve an accurate location very close to the traditional KF tracking scheme, but also has a lower computational complexity.

A Forward–Backward Approach for Instantaneous Frequency Estimation of Frequency Modulated Signals in Noisy Environment

In this paper a forward–backward basis function approach for instantaneous frequency estimation of the frequency-modulated signal in noisy environment is presented. At first, a forward–backward prediction approach is applied for least squares estimation of time-varying autoregressive parameters. A time-varying parameters are expressed as a summation of constants multiplied by basis functions. Then, the time-varying frequencies are extracted from the time-varying autoregressive parameters by calculating the angles of the estimation error filter polynomial roots. The experimental results are presented, which shows the superiority of the proposed method against the covariance (forward prediction) approach.

Iris recognition using shape-guided approach and game theory

Most state-of-the-art iris recognition algorithms claim to perform with a very high recognition accuracy in a strictly controlled environment. However, their recognition accuracies significantly decrease when the acquired images are affected by different noise factors including motion blur, camera diffusion, head movement, gaze direction, camera angle, reflections, contrast, luminosity, eyelid and eyelash occlusions, and problems due to contraction and dilation. The novelty of this research effort is that we propose to apply a variational model to localize the iris region belonging to given shape space using active contour method, a geometric shape prior, and the Mumford–Shah functional. This variational model is robust against noise, poor localization and weak iris/sclera boundaries. Furthermore, we apply the Modified Contribution-Selection Algorithm (MCSA) for iris feature ranking based on the Multi-Perturbation Shapley Analysis (MSA), a framework which relies on cooperative game theory to estimate the effectiveness of the features iteratively and select them accordingly, using either forward selection or backward elimination approaches. The verification and identification performance of the proposed scheme is validated using the ICE 2005, the UBIRIS Version 1, the CASIA Version 3 Interval, and WVU Nonideal datasets.

Pharmacokinetics of dexmedetomidine in Chinese post-surgical intensive care unit patients

Dexmedetomidine is a rather new drug in China. We sought to describe the pharmacokinetics of dexmedetomidine in patients requiring post-operative sedation and ventilation in our surgical intensive care unit. Twenty-two patients received post-operative infusions of dexmedetomidine at 6 μg/kg/h for 10 min, followed by 0.4 μg/kg/h for 350 min. Venous blood samples were drawn and assayed for plasma concentration. The pharmacokinetics were analysed using a nonlinear mixed-effect model with an interindividual and intraindividual error model. An initial estimation was performed to determine which of the one-, two- or three-compartment models is best to describe the concentration-time data. The covariates age, gender, weight, height, lean body mass (LBM), body surface area (BSA) and body mass index (BMI) were tested for significant effects on parameters using a stepwise forward addition and backward elimination approach. Covariate effects were judged based on changes in the objective function value (OFV). The pharmacokinetics of dexmedetomidine were best described by a three-compartment model. The model was further improved when height was a covariate of systemic clearance (Cl1), with a decrease in OFV by -13.56 (P<0.01). From the heights of 155-178 cm, Cl1 increased by approximately 143%. The final pharmacokinetic parameter values were as follows: V1 =63.4 l, V2=41.3 l, V3 =284.3 l, Cl1=0.47×(height/160 cm)(6.42) l/min, Cl2=2.43 l/min and Cl3=0.086 l/min. This study identified (i) the effect of height on the pharmacokinetics of dexmedetomidine; (ii) that there is no influence of age, gender, weight, LBM, BSA and BMI on pharmacokinetic parameters; and (iii) it established a preliminary population pharmacokinetic model for Chinese patients.

Estimating actual irrigation application by remotely sensed evapotranspiration observations

Water managers and policy makers need accurate estimates of real (actual) irrigation applications for effective monitoring of irrigation and efficient irrigation management. However, this information is not readily available at field level for larger irrigation areas. An innovative inverse modeling approach was tested for a field in an irrigation scheme in southern Spain where observed actual evapotranspiration by satellites was used to assess irrigation application amounts. The actual evapotranspiration was used as the basis for an optimization procedure using the physical based SWAP model and the parameter optimization tool PEST. To evaluate the proposed techniques two steps were taken. First, actual observed evapotranspiration from remote sensing was used to optimize two parameters of the SWAP model to determine irrigation applications. Second, a forward–backward approach was applied to test the minimum overpass return time of satellites and the required accuracy of remotely sensed actual evapotranspiration for accurate assessment of irrigation applications. Results indicate that irrigation application amounts can be estimated reasonably accurately, providing data are available at an interval of 15 days or shorter and the accuracy of the signal is 90% or higher.

Gaussian approximation for the structure function in semiclassical forward-backward initial value representations of time correlation functions

Initial value representations (IVRs) of semiclassical (SC) theory provide a general approach for adding quantum mechanical effects to classical molecular dynamics simulations of large molecular systems. Of the various versions of SC-IVR methodology for evaluating time correlation functions, the Fourier transform forward-backward (FB) approach is the simplest one that is able to describe true quantum coherence effects, so it is of considerable importance to find efficient and systematic ways for implementing it. It is shown in this paper that a Gaussian approximation for the "structure function"-the dependence of the correlation function on the (typically) momentum jump parameter-provides an efficient and accurate way for doing so. The approach is illustrated by an application to the time-dependent radial distribution function of I(2) (after photoexcitation) in a cluster of (up to 16) argon atoms.

Population Pharmacokinetics of Siplizumab (MEDI-507), a Humanized Anti-CD2 Monoclonal Antibody, in Cancer Patients.

Abstract 2670Poster Board II-646 Introduction:Siplizumab, a humanized IgG1k class monoclonal antibody that targets CD2 expressing T-and NK-cells, was evaluated in phase I dose-escalation trials in patients with CD2-positive lymphoproliferative disorder. The objective of this study was to develop a population pharmacokinetic (PK) model for siplizumab and identify covariates that could explain the variability in siplizumab pharmacokinetic parameters. Methods:A Phase 1, open label, dose-escalation study was conducted in 29 patients (14 males/15 females, age range 34–79 years) who received 0.2–4.8 mg/kg of siplizumab as 1-3 consecutive daily doses every 14 days for a total of 1-8 cycles. Siplizumab serum concentration data was analyzed using a nonlinear mixed effects modeling approach with software (NONMEM). Based on exploratory analysis, 1-and 2-compartment non-linear models were evaluated. Demographic covariates including body weight, age, sex and race (Caucasian/Black/Asian) were screened using Generalized Additive Model (GAM) analysis. Covariates selected during the GAM analysis were further tested for significance in NONMEM using the forward inclusion and backward elimination approach. Results:Siplizumab concentrations were obtained from all 29 patients in the study yielding a total of 619 serum concentration observations. Pronounced non-linearity in siplizumab serum concentrations was observed after the initial and later dosing cycles, with serum concentrations declining faster at lower dose levels. The data was best described by a two-compartment pharmacokinetic model with zero-order input with parallel linear and non-linear elimination pathways. Goodness of fit plots and model diagnostics indicated good agreement between observed and model predicted serum concentration values. The population estimates for linear clearance was 0.168 L/day with inter-subject variability (ISV) of 50%, and inter-compartmental clearance was 2.83 L/day. Nonlinear elimination parameters, Vmax and Km were 10.32 mcg/day (56% ISV) and 51.8 mcg/L, respectively. Sex of the patients was identified as a significant covariate impacting volumes of distribution. Male patients had higher central and peripheral volumes of distribution of 2.8 L and 3.0 L, respectively, compared to1.38 L and 2.4 L in females [32% vs 50% ISV]. Conclusion:The serum concentration-time profile of siplizumab was adequately described by a two-compartment non-linear PK model. Population parameters were precisely estimated and correspond well to reported PK behaviour of monocolonal antibodies with significant target mediated elimination. The lower volume distribution in females is most likely due to lower body weight compared to males in this study. The population PK model combined with pharmacodynamic data could serve as a tool to guide selection of optimal dose regimens for siplizumab. Disclosures:No relevant conflicts of interest to declare.

A comparison between different semiclassical approximations for optical response functions in nonpolar liquid solution. II. The signature of excited state dynamics on two-dimensional spectra

Optical response functions are known to reflect quantum dynamics in a superposition state and as such, lack a well-defined classical limit. In a previous paper we considered the importance of accounting for the quantum nature of the dynamics by comparing the linear absorption spectrum and homodyne-detected time-integrated two-pulse photon-echo signal as calculated via the semiclassical forward-backward approach, linearized semiclassical approach, and standard approach which is based on equilibrium ground state dynamics [Shi and Geva, J. Chem. Phys. 122, 064506 (2005)]. In the present paper, we extend the comparison to the case of heterodyne-detected and time-resolved nonlinear time-domain rephasing and nonrephasing signals generated in three-pulse experiments and the corresponding frequency-domain two-dimensional spectra. The comparison is performed in the context of a two-state chromophore solvated in a nonpolar liquid. It is shown that the inherent insensitivity of the standard method to the nonequilibrium dynamics on the excited state potential surface gives rise to two-dimensional spectra which are symmetrical relative to the diagonal. In contrast, accounting for the effect of nonequilibrium excited state dynamics, as is the case within the forward-backward and linearized semiclassical methods, is found to give rise to two-dimensional spectra that become increasingly asymmetrical relative to the diagonal as the waiting time between the second and third pulses becomes larger. It is argued that the emergence of the asymmetry provides a useful probe of nonequilibrium solvation on the excited state potential surface.

Some Factors Affecting Reproductive Success in Crossbred Dairy Cows on Smallholder Farms in Coastal North-East Tanzania

A 2-year longitudinal survey was carried out to investigate factors affecting reproduction in crossbred cows on smallholder farms in and around an urban centre. Sixty farms were visited at approximately 2-week intervals and details of reproductive traits and body condition score (BCS) were collected. Fifteen farms were within the town (U), 23 farms were approximately 5 km from town (SU). and 22 farms approximately 10 km from town (PU). Sources of variation in reproductive traits were investigated using a general linear model (GLM) by a stepwise forward selection and backward elimination approach to judge important independent variables. Factors considered for the first step of formulation of the model included location (PU, SU and U), type of insemination, calving season, BCS at calving, at 3 months postpartum and at 6 months postpartum, calving year, herd size category, source of labour (hired and family labour), calf rearing method (bucket and partial suckling) and parity number of the cow. The effects of the independent variables identified were then investigated using a non-parametric survival technique. The number of days to first oestrus was increased on the U site (p = 0.045) and when family labour was used (p = 0.02). The non-parametric test confirmed the effect of site (p = 0.059), but effect of labour was not significant. The number of days from calving to conception was reduced by hiring labour (p = 0.003) and using natural service (p = 0.028). The non-parametric test confirmed the effects of type of insemination (p = 0.0001) while also identifying extended calving intervals on U and SU sites (p = 0.014). Labour source was again non-significant. Calving interval was prolonged on U and SU sites (p = 0.021), by the use of AI (p = 0.031) and by the use of family labour (p = 0.001). The nonparametric test confirmed the effect of site (p = 0.008) and insemination type (p > 0.0001) but not of labour source. It was concluded that under favourable conditions (PU site, hired labour and natural service) calving intervals of around 440 days could be achieved.

Some Factors Affecting Variation in Milk Yield in Crossbred Dairy Cows on Smallholder Farms in North-East Tanzania

A 2-year longitudinal survey was carried out to investigate factors affecting milk yield in crossbred cows on smallholder farms in and around an urban centre. Sixty farms were visited at approximately 2-week intervals and details of milk yield, body condition score (BCS) and heart girth measurements were collected. Fifteen farms were within the town (U), 23 farms were approximately 5 km from town (SU), and 22 farms approximately 10 km from town (PU). Sources of variation in milk yield were investigated using a general linear model by a stepwise forward selection and backward elimination approach to judge important independent variables. Factors considered for the first step of formulation of the model included location (PU, SU and U), calving season, BCS at calving, at 3 months postpartum and at 6 months postpartum, calving year, herd size category, source of labour (hired and family labour), calf rearing method (bucket and partial suckling) and parity number of the cow. Daily milk yield (including milk sucked by calves) was determined by calving year (p < 0.0001), calf rearing method (p = 0.044) and BCS at calving (p < 0.0001). Only BCS at calving contributed to variation in volume of milk sucked by the calf, lactation length and lactation milk yield. BCS at 3 months after calving was improved on farms where labour was hired (p = 0.041) and BCS change from calving to 6 months was more than twice as likely to be negative on U than SU and PU farms. It was concluded that milk production was predominantly associated with BCS at calving, lactation milk yield increasing quadratically from score 1 to 3. BCS at calving may provide a simple, single indicator of the nutritional status of a cow population.

A comparison between different semiclassical approximations for optical response functions in nonpolar liquid solutions

The temporal behavior of optical response functions (ORFs) reflects the quantum dynamics of an electronic superposition state, and as such lacks a well-defined classical limit. In this paper, we consider the importance of accounting for the quantum nature of the dynamics when calculating ORFs of different types. To this end, we calculated the ORFs associated with the linear absorption spectrum and the nonlinear two-pulse photon-echo experiment, via the following approaches: (1) the semiclassical forward-backward approach; (2) an approach based on linearizing the path-integral forward-backward action in terms of the difference between the forward and backward paths; (3) an approach based on ground state nuclear dynamics. The calculations were performed on a model that consists of a two-state chromophore solvated in a nonpolar liquid. The different methods were found to yield very similar results for the absorption spectrum and "diagonal" two-pulse photon echo (i.e., the homodyne-detected signal at time t=t(0) after the second pulse, where t(0) is the time interval between the two pulses). The different approximations yielded somewhat different results in the case of the time-integrated photon-echo signal. The reasons for the similarity between the predictions of different approximations are also discussed.

Decoherence in an anharmonic oscillator coupled to a thermal environment: A semiclassical forward-backward approach

The decoherence of an anharmonic oscillator in a thermal harmonic bath is examined via a semiclassical approach. A computational strategy is presented and exploited to calculate the time dependence of the purity and the decay of individual matrix elements in the energy representation for a variety of initial states. The time dependence of the decoherence is found to depend on the temperature of the bath, the coupling strength, the initial state of the oscillator, and the choice of quantity measuring the decoherence. Recurrences in the purity and in the off-diagonal matrix elements are observed, as well as the collapse of these matrix elements to the diagonal, providing evidence for the retention of quantum coherence for time scales longer than that indicated by the purity. The results are used to analyze the utility of the Caldeira-Leggett and Redfield models of decoherence and to assess the dependence of dephasing rates on the degree of structure in phase space. In several cases we find that the dephasing dynamics can be described as an initial Zeno-effect regime, followed by a Caldeira-Leggett region, followed by recurrences.

Scattering From Natural Soils Modeled by Dielectric Fractal Profiles: The Forward–Backward Approach

The forward-backward (FB) method is an efficient technique for numerical evaluation of electromagnetic scattering from rough surfaces. In its usual formulation, this technique can be only applied to perfectly or highly conducting surfaces. In addition, up to now FB has been employed to compute scattering from surfaces modeled by Gaussian stochastic processes with Gaussian or Pierson-Moscowitz spectra. Accordingly, this technique can be fruitfully used for numerical simulations of scattering from sea surfaces. However, in order to properly deal with natural soil surfaces, extension to the dielectric interface case and to fractal surface models is needed. Extension of the FB method to the dielectric interface case has been recently presented, whereas application to fractal surface models is presented here. Original contribution of the present paper is twofold. First of all, the FB method for dielectric profiles is framed within the theory of iterative methods for the solution of linear systems. In addition, application of the FB method to dielectric band-limited fractional Brownian motion fractal one-dimensional surfaces is explored. Numerical experiments show that, for most of realistic values of dielectric constant and fractal parameters actually encountered for natural soil profiles, the FB method is very rapidly convergent, and its results are in perfect agreement with "exact" ones (i.e. with results of method of moments solved via a direct method).

Inverse modelling in estimating soil hydraulic functions: a Genetic Algorithm approach

Abstract. The practical application of simulation models in the field is sometimes hindered by the difficulty of deriving the soil hydraulic properties of the study area. The procedure so-called inverse modelling has been investigated in many studies to address the problem where most of the studies were limited to hypothetical soil profile and soil core samples in the laboratory. Often, the numerical approach called forward-backward simulation is employed to generate synthetic data then added with random errors to mimic the real-world condition. Inverse modelling is used to backtrack the expected values of the parameters. This study explored the potential of a Genetic Algorithm (GA) to estimate inversely the soil hydraulic functions in the unsaturated zone. Lysimeter data from a wheat experiment in India were used in the analysis. Two cases were considered: (1) a numerical case where the forward-backward approach was employed and (2) the experimental case where the real data from the lysimeter experiment were used. Concurrently, the use of soil water, evapotranspiration (ET) and the combination of both were investigated as criteria in the inverse modelling. Results showed that using soil water as a criterion provides more accurate parameter estimates than using ET. However, from a practical point of view, ET is more attractive as it can be obtained with reasonable accuracy on a regional scale from remote sensing observations. The experimental study proved that the forward-backward approach does not take into account the effects of model errors. The formulation of the problem is found to be critical for a successful parameter estimation. The sensitivity of parameters to the objective function and their zone of influence in the soil column are major determinants in the solution. Generally, their effects sometimes lead to non-uniqueness in the solution but to some extent are partly handled by GA. Overall, it was concluded that the GA approach is promising to the inverse problem in the unsaturated zone. Keywords. Genetic Algorithm, inverse modelling, Mualem-Van Genuchten parameters, unsaturated zone, evapotranspiration, soil water

A numerical study of backscattering from time-evolving sea surfaces: comparison of hydrodynamic models

Results from a Monte Carlo simulation of backscattering from one-dimensional (1-D) time-evolving sea surface models are reported. A numerical electromagnetic method based on an accelerated forward-backward approach is used to calculate backscattered returns from impedance surface profiles at incidence angles of 0/spl deg/ (normal), 40/spl deg/, and 80/spl deg/. Surfaces are initialized as realizations of a Pierson-Moskowitz spectrum and then stepped in time through a numerical hydrodynamic method. Results from three distinct hydrodynamic methods are compared: a linear evolution, the "improved linear representation" of Creamer et al. (1989), and the "Watson-West" approach of West et al. (1987). Instabilities in the West model due to formation of steep wave features limit the study to L-band backscattering for wind speeds less than 2 m/s, so that the surfaces considered are only slightly rough on an electromagnetic scale. The small slope approximation for electromagnetic scattering is shown to provide reasonable predictions in this limit. Statistics of the resulting surface profiles and backscattered fields are compared for the three models and are found to be similar in most respects. Backscattered field Doppler spectra, however, show differences, with the West model apparently capturing more nonlinear interactions in the surface evolution.

Nearest Route Problem

In this paper we propose a new class of optimization problems on oriented graphs with weight, which are called nearest route problems. A nearest problem has a target value, which generates an error function in a sense. Which route is nearest to the designated value? The nearest route problem includes both the shortest route problem and longest one. We give an invariant imbedding solution through both forward-backward and backward-forward approaches. A typical nearest problem is solved by both approaches.

A spatial interpolation algorithm for the upsampling of uniform linear arrays

A method to spatially interpolate (upsample) a uniform linear array (ULA) originally sampled at less than the spatial Nyquist rate in the presence of noise is considered. The multichannel narrowband interpolation algorithm is based on a forward-backward linear prediction approach. The method interpolates N-1 virtual sensor outputs based on the outputs of N real sensors. This is done by solving a set of forward-backward linear prediction equations that relate the known (real) sensor outputs to the unknown (virtual) sensor outputs. Simulation results that validate the performance and usefulness of this method are presented in the context of code division multiple access (CDMA) mobile communications. The algorithm is applied to increase the user capacity and resolution and decrease the mutual coupling of ULA's used in conjunction with cellular CDMA systems.

On Forward–Backward MODE for Array Signal Processing

We apply the MODE (method of direction estimation) principle to the forward–backward (FB) covariance of the output vector of a sensor array to obtain what we call the FB-MODE procedure. The derivation of FB-MODE is an interesting exercise in matrix analysis, the outcome of which was somewhat unexpected: FB-MODE simply consists of applying the standard MODE approach to the eigenelements of the FB sample covariance matrix. By using an asymptotic expansion technique we also establish the surprising result that FB-MODE is outperformed, from a statistical standpoint, by the standard MODE applied to the forward-only sample covariance (F-MODE). We believe this to be an important result that shows that the FB approach, which proved quite useful for improving the performance of many suboptimal array processing methods, should notbe used with a statistically optimal method such as F-MODE.