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In environmental epidemiology, there is wide interest in creating and using comprehensive indices that can summarize information from different environmental exposures while retaining strong predictive power on a target health outcome. In this context, the present article proposes a model called the constrained groupwise additive index model (CGAIM) to create easy-to-interpret indices predictive of a response variable, from a potentially large list of variables. The CGAIM considers groups of predictors that naturally belong together to yield meaningful indices. It also allows the addition of linear constraints on both the index weights and the form of their relationship with the response variable to represent prior assumptions or operational requirements. We propose an efficient algorithm to estimate the CGAIM, along with index selection and inference procedures. A simulation study shows that the proposed algorithm has good estimation performances, with low bias and variance and is applicable in complex situations with many correlated predictors. It also demonstrates important sensitivity and specificity in index selection, but non-negligible coverage error on constructed confidence intervals. The CGAIM is then illustrated in the construction of heat indices in a health warning system context. We believe the CGAIM could become useful in a wide variety of situations, such as warning systems establishment, and multipollutant or exposome studies.
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Algoritmos , Exposición a Riesgos Ambientales , Humanos , Exposición a Riesgos Ambientales/efectos adversos , Simulación por Computador , SesgoRESUMEN
We consider estimation of the semiparametric additive hazards model with an unspecified baseline hazard function where the effect of a continuous covariate has a specific shape but otherwise unspecified. Such estimation is particularly useful for a unimodal hazard function, where the hazard is monotone increasing and monotone decreasing with an unknown mode. A popular approach of the proportional hazards model is limited in such setting due to the complicated structure of the partial likelihood. Our model defines a quadratic loss function, and its simple structure allows a global Hessian matrix that does not involve parameters. Thus, once the global Hessian matrix is computed, a standard quadratic programming method can be applicable by profiling all possible locations of the mode. However, the quadratic programming method may be inefficient to handle a large global Hessian matrix in the profiling algorithm due to a large dimensionality, where the dimension of the global Hessian matrix and number of hypothetical modes are the same order as the sample size. We propose the quadratic pool adjacent violators algorithm to reduce computational costs. The proposed algorithm is extended to the model with a time-dependent covariate with monotone or U-shape hazard function. In simulation studies, our proposed method improves computational speed compared to the quadratic programming method, with bias and mean square error reductions. We analyze data from a recent cardiovascular study.
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Algoritmos , Humanos , Modelos de Riesgos Proporcionales , Simulación por Computador , Probabilidad , Sesgo , Funciones de VerosimilitudRESUMEN
Autonomous Underwater Vehicles (AUVs) play a significant role in ocean-related research fields as tools for human exploration and the development of marine resources. However, the uncertainty of the underwater environment and the complexity of underwater motion pose significant challenges to the fault-tolerant control of AUV actuators. This paper presents a fault-tolerant control strategy for AUV actuators based onTakagi and Sugeno (T-S) fuzzy logic and pseudo-inverse quadratic programming under control constraints, aimed at addressing potential actuator faults. Firstly, considering the steady-state performance and dynamic performance of the control system, a T-S fuzzy controller is designed. Next, based on the redundant configuration of the actuators, the propulsion system is normalized, and the fault-tolerant control of AUV actuators is achieved using the pseudo-inverse method under thrust allocation. When control is constrained, a quadratic programming approach is used to compensate for the input control quantity. Finally, the effectiveness of the fuzzy control and fault-tolerant control allocation methods studied in this paper is validated through mathematical simulation. The experimental results indicate that in various fault scenarios, the pseudo-inverse combined with a nonlinear quadratic programming algorithm can compensate for the missing control inputs due to control constraints, ensuring the normal thrust of AUV actuators and achieving the expected fault-tolerant effect.
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BACKGROUND: Flux Balance Analysis (FBA) is a key metabolic modeling method used to simulate cellular metabolism under steady-state conditions. Its simplicity and versatility have led to various strategies incorporating transcriptomic and proteomic data into FBA, successfully predicting flux distribution and phenotypic results. However, despite these advances, the untapped potential lies in leveraging gene-related connections like co-expression patterns for valuable insights. RESULTS: To fill this gap, we introduce ICON-GEMs, an innovative constraint-based model to incorporate gene co-expression network into the FBA model, facilitating more precise determination of flux distributions and functional pathways. In this study, transcriptomic data from both Escherichia coli and Saccharomyces cerevisiae were integrated into their respective genome-scale metabolic models. A comprehensive gene co-expression network was constructed as a global view of metabolic mechanism of the cell. By leveraging quadratic programming, we maximized the alignment between pairs of reaction fluxes and the correlation of their corresponding genes in the co-expression network. The outcomes notably demonstrated that ICON-GEMs outperformed existing methodologies in predictive accuracy. Flux variabilities over subsystems and functional modules also demonstrate promising results. Furthermore, a comparison involving different types of biological networks, including protein-protein interactions and random networks, reveals insights into the utilization of the co-expression network in genome-scale metabolic engineering. CONCLUSION: ICON-GEMs introduce an innovative constrained model capable of simultaneous integration of gene co-expression networks, ready for board application across diverse transcriptomic data sets and multiple organisms. It is freely available as open-source at https://github.com/ThummaratPaklao/ICOM-GEMs.git .
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Proteómica , Biología de Sistemas , Genoma , Ingeniería Metabólica , Perfilación de la Expresión Génica , Escherichia coli/genética , Escherichia coli/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Modelos Biológicos , Redes y Vías Metabólicas/genética , Análisis de Flujos Metabólicos/métodosRESUMEN
Alternative transcription units (ATUs) are dynamically encoded under different conditions and display overlapping patterns (sharing one or more genes) under a specific condition in bacterial genomes. Genome-scale identification of ATUs is essential for studying the emergence of human diseases caused by bacterial organisms. However, it is unrealistic to identify all ATUs using experimental techniques because of the complexity and dynamic nature of ATUs. Here, we present the first-of-its-kind computational framework, named SeqATU, for genome-scale ATU prediction based on next-generation RNA-Seq data. The framework utilizes a convex quadratic programming model to seek an optimum expression combination of all of the to-be-identified ATUs. The predicted ATUs in Escherichia coli reached a precision of 0.77/0.74 and a recall of 0.75/0.76 in the two RNA-Sequencing datasets compared with the benchmarked ATUs from third-generation RNA-Seq data. In addition, the proportion of 5'- or 3'-end genes of the predicted ATUs, having documented transcription factor binding sites and transcription termination sites, was three times greater than that of no 5'- or 3'-end genes. We further evaluated the predicted ATUs by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses. The results suggested that gene pairs frequently encoded in the same ATUs are more functionally related than those that can belong to two distinct ATUs. Overall, these results demonstrated the high reliability of predicted ATUs. We expect that the new insights derived by SeqATU will not only improve the understanding of the transcription mechanism of bacteria but also guide the reconstruction of a genome-scale transcriptional regulatory network.
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Biología Computacional/métodos , Estudio de Asociación del Genoma Completo/métodos , Isoformas de ARN , Transcripción Genética , Algoritmos , Bacterias/genética , Bases de Datos Genéticas , Escherichia coli/genética , Genoma Bacteriano , Genómica/métodos , Humanos , ARN Mensajero/genética , RNA-Seq , Análisis de la Célula Individual/métodos , Regiones Terminadoras Genéticas , Sitio de Iniciación de la TranscripciónRESUMEN
BACKGROUND: Inequalities in access to stroke care and the workload of physicians have been a challenge in recent times. This may be resolved by allocating physicians suitable for the expected demand. Therefore, this study analyzes whether reallocation using an optimization model reduces disparities in spatial access to healthcare and excessive workload. METHODS: This study targeted neuroendovascular specialists and primary stroke centers in Japan and employed an optimization model for reallocating neuroendovascular specialists to reduce the disparity in spatial accessibility to stroke treatment and workload for neuroendovascular specialists in Japan. A two-step floating catchment area method and an inverted two-step floating catchment area method were used to estimate the spatial accessibility and workload of neuroendovascular specialists as a potential crowdedness index. Quadratic programming has been proposed for the reallocation of neuroendovascular specialists. RESULTS: The reallocation of neuroendovascular specialists reduced the disparity in spatial accessibility and the potential crowdedness index. The standard deviation (SD) of the demand-weighted spatial accessibility index improved from 125.625 to 97.625. Simultaneously, the weighted median spatial accessibility index increased from 2.811 to 3.929. Additionally, the SD of the potential crowdedness index for estimating workload disparity decreased from 10,040.36 to 5934.275 after optimization. The sensitivity analysis also showed a similar trend of reducing disparities. CONCLUSIONS: The reallocation of neuroendovascular specialists reduced regional disparities in spatial accessibility to healthcare, potential crowdedness index, and disparities between facilities. Our findings contribute to planning health policies to realize equity throughout the healthcare system.
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Médicos , Accidente Cerebrovascular , Humanos , Carga de Trabajo , Accesibilidad a los Servicios de Salud , Accidente Cerebrovascular/terapia , Instituciones de SaludRESUMEN
In the context of Minimally Invasive Surgery, surgeons mainly rely on visual feedback during medical operations. In common procedures such as tissue resection, the automation of endoscopic control is crucial yet challenging, particularly due to the interactive dynamics of multi-agent operations and the necessity for real-time adaptation. This paper introduces a novel framework that unites a Hierarchical Quadratic Programming controller with an advanced interactive perception module. This integration addresses the need for adaptive visual field control and robust tool tracking in the operating scene, ensuring that surgeons and assistants have optimal viewpoint throughout the surgical task. The proposed framework handles multiple objectives within predefined thresholds, ensuring efficient tracking even amidst changes in operating backgrounds, varying lighting conditions, and partial occlusions. Empirical validations in scenarios involving single, double, and quadruple tool tracking during tissue resection tasks have underscored the system's robustness and adaptability. The positive feedback from user studies, coupled with the low cognitive and physical strain reported by surgeons and assistants, highlight the system's potential for real-world application.
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Endoscopios , Procedimientos Quirúrgicos Mínimamente Invasivos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Endoscopía/métodos , Automatización , PercepciónRESUMEN
Minimally invasive surgery has undergone significant advancements in recent years, transforming various surgical procedures by minimizing patient trauma, postoperative pain, and recovery time. However, the use of robotic systems in minimally invasive surgery introduces significant challenges related to the control of the robot's motion and the accuracy of its movements. In particular, the inverse kinematics (IK) problem is critical for robot-assisted minimally invasive surgery (RMIS), where satisfying the remote center of motion (RCM) constraint is essential to prevent tissue damage at the incision point. Several IK strategies have been proposed for RMIS, including classical inverse Jacobian IK and optimization-based approaches. However, these methods have limitations and perform differently depending on the kinematic configuration. To address these challenges, we propose a novel concurrent IK framework that combines the strengths of both approaches and explicitly incorporates RCM constraints and joint limits into the optimization process. In this paper, we present the design and implementation of concurrent inverse kinematics solvers, as well as experimental validation in both simulation and real-world scenarios. Concurrent IK solvers outperform single-method solvers, achieving a 100% solve rate and reducing the IK solving time by up to 85% for an endoscope positioning task and 37% for a tool pose control task. In particular, the combination of an iterative inverse Jacobian method with a hierarchical quadratic programming method showed the highest average solve rate and lowest computation time in real-world experiments. Our results demonstrate that concurrent IK solving provides a novel and effective solution to the constrained IK problem in RMIS applications.
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Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Fenómenos Biomecánicos , Procedimientos Quirúrgicos Robotizados/métodos , Movimiento (Física) , Procedimientos Quirúrgicos Mínimamente Invasivos/métodosRESUMEN
In order to improve the real-time performance of the trajectory tracking of autonomous vehicles, this paper applies the alternating direction multiplier method (ADMM) to the receding optimization of model predictive control (MPC), which improves the computational speed of the algorithm. Based on the vehicle dynamics model, the output equation of the autonomous vehicle trajectory tracking control system is constructed, and the auxiliary variable and the dual variable are introduced. The quadratic programming problem transformed from the MPC and the vehicle dynamics constraints are rewritten into the solution of the ADMM form, and a decreasing penalty factor is used during the solution process. The simulation verification is carried out through the joint simulation platform of Simulink and Carsim. The results show that, compared with the active set method (ASM) and the interior point method (IPM), the algorithm proposed in this paper can not only improve the accuracy of trajectory tracking, but also exhibits good real-time performance in different prediction time domains and control time domains. When the prediction time domain increases, the calculation time shows no significant difference. This verifies the effectiveness of the ADMM in improving the real-time performance of MPC.
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The paper describes an application of the p-regularity theory to Quadratic Programming (QP) and nonlinear equations with quadratic mappings. In the first part of the paper, a special structure of the nonlinear equation and a construction of the 2-factor operator are used to obtain an exact formula for a solution to the nonlinear equation. In the second part of the paper, the QP problem is reduced to a system of linear equations using the 2-factor operator. The solution to this system represents a local minimizer of the QP problem along with its corresponding Lagrange multiplier. An explicit formula for the solution of the linear system is provided. Additionally, the paper outlines a procedure for identifying active constraints, which plays a crucial role in constructing the linear system.
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Effective river water quality management and planning is a complex issue challenged by various complexities and uncertainties. A simulation-based interval chance-constrained quadratic programming (ICCQP) model is developed for the seasonal planning of water quality management (WQM) under various uncertainties. The proposed model incorporates interval quadratic programming, chance-constrained programming, and a seasonal water quality simulation model within a general framework for WQM. Uncertainties associated with the objective and the coefficients in the left-hand sides of the constraints are tackled as intervals. Meanwhile, parameter uncertainties on the right-hand sides are characterized using probability distributions. Nonlinearities in the cost function are reflected by quadratic programming. A multi-segment water quality model is used to simulate the dynamic interactions between wastewater discharges and river water quality. The proposed ICCQP-WQM model is applied in a real case study for the control of total phosphorus (TP) in the central Grand River in Ontario, Canada. The results demonstrate that the proposed model is able to incorporate uncertainties expressed as intervals and probability information into an optimization framework and provide interval solutions. Thus, different cost-effective schemes for seasonal WQM could be generated. The results show the Kitchener wastewater treatment plant (WWTP) affects the value of the objective function more than the other WWTPs in the study area. It is also found that the Kitchener WWTP's cost accounts for the highest proportion (approximately 35.1-37.9%) of the total annual cost, which implies the control of TP at the Kitchener plant is the most important to the system. Moreover, river water TP standards in spring and autumn are usually difficult to meet, indicating different TP control strategies are needed in these two seasons. The generated results are valuable for local decision makers to generate TP control strategies, and also to identify optimized solutions under various uncertainties. The proposed ICCQP-WQM model can be extended to other watersheds to support effective water quality management and planning.
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Ríos , Calidad del Agua , Ontario , Probabilidad , IncertidumbreRESUMEN
The highly dynamic legged jumping motion is a challenging research topic because of the lack of established control schemes that handle over-constrained control objectives well in the stance phase, which are coupled and affect each other, and control robot's posture in the flight phase, in which the robot is underactuated owing to the foot leaving the ground. This paper introduces an approach of realizing the cyclic vertical jumping motion of a planar simplified legged robot that formulates the jump problem within a quadratic-programming (QP)-based framework. Unlike prior works, which have added different weights in front of control tasks to express the relative hierarchy of tasks, in our framework, the hierarchical quadratic programming (HQP) control strategy is used to guarantee the strict prioritization of the center of mass (CoM) in the stance phase while split dynamic equations are incorporated into the unified quadratic-programming framework to restrict the robot's posture to be near a desired constant value in the flight phase. The controller is tested in two simulation environments with and without the flight phase controller, the results validate the flight phase controller, with the HQP controller having a maximum error of the CoM in the x direction and y direction of 0.47 and 0.82 cm and thus enabling the strict prioritization of the CoM.
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In this study, we deal with the problem of scheduling charging periods of electrical vehicles (EVs) to satisfy the users' demands for energy consumption as well as to optimally utilize the available power. We assume three-phase EV charging stations, each equipped with two charging ports (links) that can serve up to two EVs in the scheduling period but not simultaneously. Considering such a specification, we propose an on-off scheduling scheme wherein control over an energy flow is achieved by flexibly switching the ports in each station on and off in a manner such as to satisfy the energy demand of each EV, flatten the high energy-consuming load on the whole farm, and to minimize the number of switching operations. To satisfy these needs, the on-off scheduling scheme is formulated in terms of a binary linear programming problem, which is then extended to a quadratic version to incorporate the smoothness constraints. Various algorithmic approaches are used for solving a binary quadratic programming problem, including the Frank-Wolfe algorithm and successive linear approximations. The numerical simulations demonstrate that the latter is scalable, efficient, and flexible in a charging procedure, and it shaves the load peak while maintaining smooth charging profiles.
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To track moving targets undergoing unknown translational and rotational motions, a tracking controller is developed for unmanned aerial vehicles (UAVs). The main challenges are to control both the relative position and orientation between the target and the UAV to within desired values, and to guarantee that the generated control input to the UAV is feasible (i.e., below its motion capability). Moreover, the UAV is controlled to ensure that the target always remains within the field of view of the onboard camera. These control objectives were achieved by developing a nonlinear-model predictive controller, in which the future motion of the target is predicted by quadratic programming (QP). Since constraints of the feature vector and the control input are considered when solving the optimal control problem, the control inputs can be bounded and the target can remain inside the image. Three simulations were performed to compare the efficacy and performance of the developed controller with a traditional image-based visual servoing controller.
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Underwater vehicles (UVs) are subjected to various environmental disturbances due to ocean currents, propulsion systems, and un-modeled disturbances. In practice, it is very challenging to design a control system to maintain UVs stayed at the desired static position permanently under these conditions. Therefore, in this study, a nonlinear dynamics and robust positioning control of the over-actuated autonomous underwater vehicle (AUV) under the effects of ocean current and model uncertainties are presented. First, a motion equation of the over-actuated AUV under the effects of ocean current disturbances is established, and a trajectory generation of the over-actuated AUV heading angle is constructed based on the line of sight (LOS) algorithm. Second, a dynamic positioning (DP) control system based on motion control and an allocation control is proposed. For this, motion control of the over-actuated AUV based on the dynamic sliding mode control (DSMC) theory is adopted to improve the system robustness under the effects of the ocean current and model uncertainties. In addition, the stability of the system is proved based on Lyapunov criteria. Then, using the generalized forces generated from the motion control module, two different methods for optimal allocation control module: the least square (LS) method and quadratic programming (QP) method are developed to distribute a proper thrust to each thruster of the over-actuated AUV. Simulation studies are conducted to examine the effectiveness and robustness of the proposed DP controller. The results show that the proposed DP controller using the QP algorithm provides higher stability with smaller steady-state error and stronger robustness.
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PURPOSE: This paper proposes a methodology and a computational tool to study the COVID-19 pandemic throughout the world and to perform a trend analysis to assess its local dynamics. METHODS: Mathematical functions are employed to describe the number of cases and demises in each region and to predict their final numbers, as well as the dates of maximum daily occurrences and the local stabilization date. The model parameters are calibrated using a computational methodology for numerical optimization. Trend analyses are run, allowing to assess the effects of public policies. Easy to interpret metrics over the quality of the fitted curves are provided. Country-wise data from the European Centre for Disease Prevention and Control (ECDC) concerning the daily number of cases and demises around the world are used, as well as detailed data from Johns Hopkins University and from the Brasil.io project describing individually the occurrences in United States counties and in Brazilian states and cities, respectively. U. S. and Brazil were chosen for a more detailed analysis because they are the current focus of the pandemic. RESULTS: Illustrative results for different countries, U. S. counties and Brazilian states and cities are presented and discussed. CONCLUSION: The main contributions of this work lie in (i) a straightforward model of the curves to represent the data, which allows automation of the process without requiring interventions from experts; (ii) an innovative approach for trend analysis, whose results provide important information to support authorities in their decision-making process; and (iii) the developed computational tool, which is freely available and allows the user to quickly update the COVID-19 analyses and forecasts for any country, United States county or Brazilian state or city present in the periodic reports from the authorities.
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A unipolar electrohydrodynamic (UP-EHD) pump flow is studied with known electric potential at the emitter and zero electric potential at the collector. The model is designed for electric potential, charge density, and electric field. The dimensionless parameters, namely the electrical source number (Es), the electrical Reynolds number (ReE), and electrical slip number (Esl), are considered with wide ranges of variation to analyze the UP-EHD pump flow. To interpret the pump flow of the UP-EHD model, a hybrid metaheuristic solver is designed, consisting of the recently developed technique sine-cosine algorithm (SCA) and sequential quadratic programming (SQP) under the influence of an artificial neural network. The method is abbreviated as ANN-SCA-SQP. The superiority of the technique is shown by comparing the solution with reference solutions. For a large data set, the technique is executed for one hundred independent experiments. The performance is evaluated through performance operators and convergence plots.
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In this work, an important model in fluid dynamics is analyzed by a new hybrid neurocomputing algorithm. We have considered the Falkner-Skan (FS) with the stream-wise pressure gradient transfer of mass over a dynamic wall. To analyze the boundary flow of the FS model, we have utilized the global search characteristic of a recently developed heuristic, the Sine Cosine Algorithm (SCA), and the local search characteristic of Sequential Quadratic Programming (SQP). Artificial neural network (ANN) architecture is utilized to construct a series solution of the mathematical model. We have called our technique the ANN-SCA-SQP algorithm. The dynamic of the FS system is observed by varying stream-wise pressure gradient mass transfer and dynamic wall. To validate the effectiveness of ANN-SCA-SQP algorithm, our solutions are compared with state-of-the-art reference solutions. We have repeated a hundred experiments to establish the robustness of our approach. Our experimental outcome validates the superiority of the ANN-SCA-SQP algorithm.
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Background and objectives: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread to more than 200 countries. In light of this situation, the Japanese Government declared a state of emergency in seven regions of Japan on 7 April 2020 under the provisions of the law. The medical care delivery system has been under pressure. Although various surgical societies have published guidelines on which to base their surgical decisions, it is not clear how general anesthesia has been performed and will be performed in Japan. Materials and Methods: One of the services provided by the social network service Twitter is a voting function-Twitter Polls-through which anonymous surveys were conducted. We analyzed the results of a series of surveys 17 times over 22 weeks on Twitter on the status of operating restrictions using quadratic programming to solve the mathematical optimizing problem, and public data provided by the Japanese Government were used to estimate the current changes in the number of general anesthesia performed in Japan. Results: The minimum number of general anesthesia cases per week was estimated at 67.1% compared to 2015 on 27 April 2020. The timeseries trend was compatible with the results reported by the Japanese Society of Anesthesiologists (correlation coefficient r = 0.69, p < 0.001). Conclusions: The number of general anesthesia was reduced up to two-thirds during the pandemic of COVID-19 in Japan and was successfully quantitatively estimated using a quick questionnaire on Twitter.
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Anestesia General/estadística & datos numéricos , Anestesiología/estadística & datos numéricos , COVID-19 , Utilización de Instalaciones y Servicios/estadística & datos numéricos , Medios de Comunicación Sociales/estadística & datos numéricos , Humanos , Japón , Cómputos Matemáticos , Proyectos de Investigación , SARS-CoV-2 , Sociedades Médicas/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
BACKGROUND: The population attributable fraction (PAF) is the fraction of disease cases in a sample that can be attributed to an exposure. Estimating the PAF often involves the estimation of the probability of having the disease given the exposure while adjusting for confounders. In many settings, the exposure can interact with confounders. Additionally, the exposure may have a monotone effect on the probability of having the disease, and this effect is not necessarily linear. METHODS: We develop a semiparametric approach for estimating the probability of having the disease and, consequently, for estimating the PAF, controlling for the interaction between the exposure and a confounder. We use a tensor product of univariate B-splines to model the interaction under the monotonicity constraint. The model fitting procedure is formulated as a quadratic programming problem, and, thus, can be easily solved using standard optimization packages. We conduct simulations to compare the performance of the developed approach with the conventional B-splines approach without the monotonicity constraint, and with the logistic regression approach. To illustrate our method, we estimate the PAF of hopelessness and depression for suicidal ideation among elderly depressed patients. RESULTS: The proposed estimator exhibited better performance than the other two approaches in the simulation settings we tried. The estimated PAF attributable to hopelessness is 67.99% with 95% confidence interval: 42.10% to 97.42%, and is 22.36% with 95% confidence interval: 12.77% to 56.49% due to depression. CONCLUSIONS: The developed approach is easy to implement and supports flexible modeling of possible non-linear relationships between a disease and an exposure of interest.