Design and nonlinear modeling of a sensitive sensor for the measurement of flow in mice.
ABSTRACT: OBJECTIVE:While many studies rely on flow and pressure measurements in small animal models of respiratory disease, such measurements can however be inaccurate and difficult to obtain. Thus, the goal of this study was to design and implement an easy-to-manufacture and accurate sensor capable of monitoring flow. APPROACH:We designed and 3D printed a flowmeter and utilized parametric (resistance and inertance) and nonparametric (polynomial and Volterra series) system identification to characterize the device. The sensor was tested in a closed system for apparent flow using the common mode rejection ratio (CMRR). The sensor properly measured tidal volumes and respiratory rates in spontaneously breathing mice. The device was used to evaluate a ventilator's ability to deliver a prescribed volume before and after lung injury. MAIN RESULTS:The parametric and polynomial models provided a reasonable prediction of the independently measured flow (Adjusted coefficient of determination [Formula: see text]??=??0.9591 and 0.9147 respectively), but the Volterra series of the 1st, 2nd, and 3rd order with a memory of six time points provided better fits ([Formula: see text]??=??0.9775, 0.9787, and 0.9954, respectively). At and below the mouse breathing frequency (1-5 Hz), CMRR was higher than 40 dB. Following lung injury, the sensor revealed a significant drop in delivered tidal volume. SIGNIFICANCE:We demonstrate that the application of nonparametric nonlinear Volterra series modeling in combination with 3D printing technology allows the inexpensive and rapid fabrication of an accurate flow sensor for continuously measuring small flows in various physiological conditions.
Project description:A transformed Bernstein polynomial that is centered at standard parametric families, such as Weibull or log-logistic, is proposed for use in the accelerated hazards model. This class provides a convenient way towards creating a Bayesian nonparametric prior for smooth densities, blending the merits of parametric and nonparametric methods, that is amenable to standard estimation approaches. For example optimization methods in SAS or R can yield the posterior mode and asymptotic covariance matrix. This novel nonparametric prior is employed in the accelerated hazards model, which is further generalized to time-dependent covariates. The proposed approach fares considerably better than previous approaches in simulations; data on the effectiveness of biodegradable carmustine polymers on recurrent brain malignant gliomas is investigated.
Project description:To characterize radiation therapy patient breathing patterns based on measured external surrogate information.Breathing surrogate data were collected during 4DCT from a cohort of 50 patients including 28 patients with lung cancer and 22 patients without lung cancer. A spirometer and an abdominal pneumatic bellows were used as the surrogates. The relationship between these measurements was assumed to be linear within a small phase difference. The signals were correlated and drift corrected using a previously published method to convert the signal into tidal volume. The airflow was calculated with a first order time derivative of the tidal volume using a window centered on the point of interest and with a window length equal to the CT gantry rotation period. The airflow was compared against the tidal volume to create ellipsoidal patterns that were binned into 25 ml × 25 ml∕s bins to determine the relative amount of time spent in each bin. To calculate the variability of the maximum inhalation tidal volume within a free-breathing scan timeframe, a metric based on percentile volume ratios was defined. The free breathing variability metric (κ) was defined as the ratio between extreme inhalation tidal volumes (defined as >93 tidal volume percentile of the measured tidal volume) and normal inhalation tidal volume (defined as >80 tidal volume percentile of the measured tidal volume).There were three observed types of volume-flow curves, labeled Types 1, 2, and 3. Type 1 patients spent a greater duration of time during exhalation with κ = 1.37 ± 0.11. Type 2 patients had equal time duration spent during inhalation and exhalation with κ = 1.28 ± 0.09. The differences between the mean peak exhalation to peak inhalation tidal volume, breathing period, and the 85th tidal volume percentile for Type 1 and Type 2 patients were statistically significant at the 2% significance level. The difference between κ and the 98th tidal volume percentile for Type 1 and Type 2 patients was found to be statistically significant at the 1% significance level. Three patients did not display a breathing stability curve that could be classified as Type 1 or Type 2 due to chaotic breathing patterns. These patients were classified as Type 3 patients.Based on an observed volume-flow curve pattern, the cohort of 50 patients was divided into three categories called Type 1, Type 2, and Type 3. There were statistically significant differences in breathing characteristics between Type 1 and Type 2 patients. The use of volume-flow curves to classify patients has been demonstrated as a physiological characterization metric that has the potential to optimize gating windows in radiation therapy.
Project description:Differences in tidal breathing patterns have been reported between patients with chronic obstructive pulmonary disease (COPD) and healthy individuals using traditional measurement techniques. This feasibility study examined whether structured light plethysmography (SLP) - a noncontact, light-based technique - could also detect differences in tidal breathing patterns between patients with COPD and healthy subjects.A 5 min period of tidal (quiet) breathing was recorded in each patient with COPD (n=31) and each healthy subject (n=31), matched for age, body mass index, and sex. For every participant, the median and interquartile range (IQR; denoting within-subject variability) of 12 tidal breathing parameters were calculated. Individual data were then combined by cohort and summarized by its median and IQR.After correction for multiple comparisons, inspiratory time (median tI) and its variability (IQR of tI) were lower in patients with COPD (p<0.001 and p<0.01, respectively) as were ratios derived from tI (tI/tE and tI/tTot, both p<0.01) and their variability (p<0.01 and p<0.05, respectively). IE50SLP (the ratio of inspiratory to expiratory flow at 50% tidal volume calculated from the SLP signal) was higher (p<0.001) in COPD while SLP-derived time to reach peak tidal expiratory flow over expiratory time (median tPTEFSLP/tE) was shorter (p<0.01) and considerably less variable (p<0.001). Thoraco-abdominal asynchrony was increased (p<0.05) in COPD.These early observations suggest that, like traditional techniques, SLP is able to detect different breathing patterns in COPD patients compared with subjects with no respiratory disease. This provides support for further investigation into the potential uses of SLP in assessing clinical conditions and interventions.
Project description:Functional data methods are often applied to longitudinal data as they provide a more flexible way to capture dependence across repeated observations. However, there is no formal testing procedure to determine if functional methods are actually necessary. We propose a goodness-of-fit test for comparing parametric covariance functions against general nonparametric alternatives for both irregularly observed longitudinal data and densely observed functional data. We consider a smoothing-based test statistic and approximate its null distribution using a bootstrap procedure. We focus on testing a quadratic polynomial covariance induced by a linear mixed effects model and the method can be used to test any smooth parametric covariance function. Performance and versatility of the proposed test is illustrated through a simulation study and three data applications.
Project description:RATIONALE:The relationship between respiratory function at hospital discharge and the severity of later respiratory disease in extremely low gestational age neonates is not well defined. OBJECTIVES:To test the hypothesis that tidal breathing measurements near the time of hospital discharge differ between extremely premature infants with bronchopulmonary dysplasia (BPD) or respiratory disease in the first year of life and those without these conditions. METHODS:Study subjects were part of the PROP (Prematurity and Respiratory Outcomes Program) study, a longitudinal cohort study of infants born at less than 29 gestational weeks followed from birth to 1 year of age. Respiratory inductance plethysmography was used for tidal breathing measurements before and after inhaled albuterol 1 week before anticipated hospital discharge. Infants were breathing spontaneously and were receiving less than or equal to 1 L/min nasal cannula flow at 21% to 100% fraction of inspired oxygen. A survey of respiratory morbidity was administered to caregivers at 3, 6, 9, and 12 months corrected age to assess for respiratory disease. We compared tidal breathing measurements in infants with and without BPD (oxygen requirement at 36 wk) and with and without respiratory disease in the first year of life. Measurements were also performed in a comparison cohort of term infants. RESULTS:A total of 765 infants survived to 36 weeks postmenstrual age, with research-quality tidal breathing data in 452 out of 564 tested (80.1%). Among these 452 infants, the rate of postdischarge respiratory disease was 65.7%. Compared with a group of 18 term infants, PROP infants had abnormal tidal breathing patterns. However, there were no clinically significant differences in tidal breathing measurements in PROP infants who had BPD or who had respiratory disease in the first year of life compared with those without these diagnoses. Bronchodilator response was not significantly associated with respiratory disease in the first year of life. CONCLUSIONS:Extremely premature infants receiving less than 1 L/min nasal cannula support at 21% to 100% fraction of inspired oxygen have tidal breathing measurements that differ from term infants, but these measurements do not differentiate those preterm infants who have BPD or will have respiratory disease in the first year of life from those who do not. Clinical trial registered with www.clinicaltrials.gov (NCT01435187).
Project description:Measurement of lung function can be difficult in young children. Structured light plethysmography (SLP) is a novel, noncontact method of measuring tidal breathing that monitors displacement of the thoraco-abdominal wall. SLP was used to compare breathing in children recovering from an acute exacerbation of asthma/wheeze and an age-matched cohort of controls. Children aged 2-12 years with acute asthma/wheeze (n = 39) underwent two 5-min SLP assessments, one before bronchodilator treatment and one after. SLP was performed once in controls (n = 54). Nonparametric comparisons of patients to healthy children and of pre-bronchodilator to post-bronchodilator were made for all children, and also stratified by age group (2-5 vs. 6-12 years old). In the asthma/wheeze group, IE50SLP (inspiratory to expiratory flow ratio) was higher (median 1.47 vs. 1.31; P = 0.002), thoraco-abdominal asynchrony (TAA) and left-right asynchrony were greater (both P < 0.001), and respiratory rate was faster (P < 0.001) than in controls. All other timing indices were shorter and displayed reduced variability (all P < 0.001). Variability in time to peak inspiratory flow was also reduced (P < 0.001). Younger children showed a greater effect than older children for TAA (interaction P < 0.05). After bronchodilator treatment, the overall cohort showed a reduction in within-subject variability in time to peak expiratory flow only (P < 0.001). Younger children exhibited a reduction in relative contribution of the thorax, TAA, and variability in TAA (interaction P < 0.05). SLP can be successfully performed in young children. The potential of SLP to monitor diseases such as asthma in children is worthy of further investigation. ClinicalTrials.gov identifier: NCT02543333.
Project description:Laryngoscopy is the gold standard to diagnose exercise-induced laryngeal obstruction, though inspiratory flow-volume loop may provide a clue. We combined tidal flow-volume loop analysis plus laryngoscopy during exercise and found that cigar-shaped - not flattened - inspiratory loops are associated with obstruction. Pursed-lip breathing slows inhalation thereby reducing vocal fold adduction.
Project description:This study sought to determine whether models of cerebrovascular function based on Laguerre-Volterra kernels that account for nonlinear cerebral blood flow (CBF) dynamics can detect the effects of functional cerebral sympathetic blockade. We retrospectively analyzed continuous beat-to-beat blood pressure, middle cerebral blood velocity, and partial-pressure of end-tidal CO2 (PETCO2) recordings from eighteen healthy individuals who were treated with either an oral dose of the ?1-adrenergic receptor blocker Prazosin or a placebo treatment. The global principal dynamic modes (PDMs) were analyzed using Laguerre-Volterra kernels to examine the nonlinear system dynamics. Our principal findings were: (1) very low frequency (<0.03 Hz) linear components of first-order kernels for BP and PETCO2 are mutually coupled to CBF dynamics with the ability to separate individuals between control and blockade conditions, and (2) the gains of the nonlinear functions associated with low-pass and ?0.03 Hz global PDMs for the BP are sensitive to sympathetic blockade. Collectively these results suggest that very low frequency global PDMs for BP may have potential utility as functional biomarkers of sympathetic neurovascular dysfunction which can occur in conditions like autonomic failure, stroke and traumatic brain injury.
Project description:Aerosolized furosemide has been shown to relieve dyspnea; nevertheless, all published studies have shown great variability in response. This dyspnea relief is thought to result from the stimulation of slowly adapting pulmonary stretch receptors simulating larger tidal volume. We hypothesized that better control over aerosol administration would produce more consistent dyspnea relief; we used a clinical ventilator to control inspiratory flow and tidal volume. Twelve healthy volunteers inhaled furosemide (40mg) or placebo in a double blind, randomized, crossover study. Breathing Discomfort was induced by hypercapnia during constrained ventilation before and after treatment. Both treatments reduced breathing discomfort by 20% full scale. Effectiveness of aerosol furosemide treatment was weakly correlated with larger tidal volume. Response to inhaled furosemide was inversely correlated to furosemide blood level, suggesting that variation among subjects in the fate of deposited drug may determine effectiveness. We conclude that control of aerosol delivery conditions does not improve consistency of treatment effect; we cannot, however, rule out placebo effect.