A Synthesis Method for Automatic Handling of Inter-patient Variability in Closed-loop Anesthesia

This paper presents a convex-optimization-based technique to obtain parameters for a PID feedback controller, used to control the infusion rate of the anesthetic drug propofol. The controller design is based on a set of identified patient models, relating propofol infusion to an EEG-based conciousness index. The main contribution lies in the method automatically taking inter-patient variability into account, i.e., it guarantees robustness (sensitivity peak) and performance (disturbance rejection) over a set of patient models, without the need for manual intervention. The method is demonstrated using a clinically relevant design example. A controller designed using the proposed method is currently scheduled for clinical evaluation

Quantification of the variability in response to propofol administration in children

Closed-loop control of anesthesia is expected to decrease drug dosage and wake up time while increasing patient safety and decreasing the work load of the anesthesiologist. The potential of closed-loop control in anesthesia has been demon- strated in several clinical studies. One of the challenges in the development of a closed-loop system that can be widely accepted by clinicians and regulatory authorities is the effect of inter- patient variability in drug sensitivity. This system uncertainty may lead to unacceptable performance, or even instability of the closed-loop system for some individuals. The development of reliable models of the effect of anesthetic drugs and charac- terization of the uncertainty is therefore an important step in the development of a closed-loop system. Model identification from clinical data is challenging due to limited excitation and the lack of validation data. In this paper, approximate models are therefore validated for controller design by evaluating the predictive accuracy of the closed-loop behavior. A set of 47 validated models that describe the inter-patient variability in the response to propofol in children is presented. This model set can be used for robust linear controller design provided that the experimental conditions are similar to the conditions during data collection

Optimizing robust PID control of propofol anesthesia for children; design and clinical evaluation

Objective: The goal of this study was to optimize robust PID control for propofol anesthesia in children aged 5-10 years to improve performance, particularly to decrease the time of induction of anesthesia while maintaining robustness.Methods: We analyzed results of a previous study conducted by our group to identify opportunities for system improvement. Allometric scaling was introduced to reduce the interpatient variability and a new robust PID controller was designed using an optimization based method. We evaluated this optimized design in a clinical study involving 16 new cases.Results: The optimized controller design achieved the performance predicted in simulation studies in the design stage. Time of induction of anesthesia was median [Q1, Q3] 3.7 [2.3, 4.1] minutes and the achieved global score was 13.4 [9.9, 16.8]. Conclusion: Allometric scaling reduces the interpatient variability in this age group, and allows for improved closed-loop performance. The uncertainty described by the model set, the predicted closedloop responses and the predicted robustness margins are realistic. The system meets the design objectives of improved speed of induction of anesthesia while maintaining robustness, improving clinically relevant system behavior.Significance: Control system optimization and ongoing system improvement are essential to the development of a clinically relevant commercial device. This paper demonstrates the validity of our approach, including system modeling, controller optimization and pre-clinical testing in simulation

The impact of depression and physical multimorbidity on health-related quality of life in China: a national longitudinal quantile regression study

The co-occurrence of mental and physical chronic conditions is a growing concern and a largely unaddressed challenge in low-and-middle-income countries. This study aimed to investigate the independent and multiplicative effects of depression and physical chronic conditions on health-related quality of life (HRQoL) in China, and how it varies by age and gender. We used two waves of the China Health and Retirement Longitudinal Study (2011, 2015), including 9227 participants aged ≥ 45 years, 12 physical chronic conditions and depressive symptoms. We used mixed-effects linear regression to assess the effects of depression and physical multimorbidity on HRQoL, which was measured using a proxy measure of Physical Component Scores (PCS) and Mental Component Scores (MCS) of the matched SF-36 measure. We found that each increased number of physical chronic conditions, and the presence of depression were independently associated with lower proxy PCS and MCS scores. There were multiplicative effects of depression and physical chronic conditions on PCS (− 0.83 points, 95% CI − 1.06, − 0.60) and MCS scores (− 0.50 points, 95% CI − 0.73, − 0.27). The results showed that HRQoL decreased markedly with multimorbidity and was exacerbated by the presence of co-existing physical and mental chronic conditions

Design and clinical evaluation of robust PID control of propofol anesthesia in children

This paper describes the design of a robust PID controller for propofol infusion in children and presents the results of clinical evaluation of this closed-loop system during endoscopic investigations in children age 6y-17y. The controller design is based on a set of models that describes the inter- patient variability in the response to propofol infusion in the study population. The PID controller is tuned to achieve sufficient robustness margins for the identified uncertainty. 108 children were enrolled in the study, anesthesia was closed-loop controlled in 102 of these cases. Clinical evaluation of the system shows that closed-loop control of both induction and maintenance of anesthesia in children based on the WAVCNS index as a measure of clinical effect is feasible. A robustly tuned PID controller can accommodate the inter-patient variability in children and spontaneous breathing can be maintained in most subjects

The contribution of exon-skipping events on chromosome 22 to protein coding diversity

Completion of the human genome sequence provides evidence for a gene count with lower bound 30,000–40,000. Significant protein complexity may derive in part from multiple transcript isoforms. Recent EST based studies have revealed that alternate transcription, including alternative splicing, polyadenylation and transcription start sites, occurs within at least 30–40% of human genes. Transcript form surveys have yet to integrate the genomic context, expression, frequency, and contribution to protein diversity of isoform variation. We determine here the degree to which protein coding diversity may be influenced by alternate expression of transcripts by exhaustive manual confirmation of genome sequence annotation, and comparison to available transcript data to accurately associate skipped exon isoforms with genomic sequence. Relative expression levels of transcripts are estimated from EST database representation. The rigorous in silico method accurately identifies exon skipping using verified genome sequence. 545 genes have been studied in this first hand-curated assessment of exon skipping on chromosome 22