Integrating Machine Learning with Biomedical Signal Processing and Systems Analysis: An Applications-based Course.

The growing importance of data analytics in biomedicine is increasingly becoming recognized in biomedical engineering curricula through the introduction of machine learning classes that generally run in parallel to, but separately from, more traditional engineering courses, such as signal and systems analysis. We propose a new approach that systematically integrates signal processing and systems analysis with key techniques in machine learning. In the proposed course, the student obtains hands-on experience in applying algorithms that can be applied to practical problems of physiological signal conditioning, analysis and interpretation.

McDAPS: A multi-channel physiological signals display and analysis system for clinical researchers.

We introduce McDAPS, an interactive software for assessing autonomic imbalance from non-invasive multi-channel physiological recordings. McDAPS provides a graphical user interface for data visualization, beat-to-beat processing and interactive analyses. The software extracts beat-to-beat RR interval systolic blood pressure, diastolic blood pressure, the pulse amplitude of photoplethysmogram and the pulse-to-pulse interval.

Functional near-infrared spectroscopy-based prefrontal cortex oxygenation during working memory tasks in sickle cell disease.

Significance: Sickle cell disease (SCD), characterized by painful vaso-occlusive crises, is associated with cognitive decline. However, objective quantification of cognitive decline in SCD remains a challenge, and the associated hemodynamics are unknown.

Aim: To address this, we utilized functional near-infrared spectroscopy (fNIRS) to measure prefrontal cortex (PFC) oxygenation responses to -back working memory tasks in SCD patients and compared them with healthy controls.

Treatment of Cheyne-Stokes Respiration in Heart Failure with Adaptive Servo-Ventilation: An Integrative Model.

The SERVE-HF (Treatment of Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure) multicenter trial found a small but significant increase in all-cause and cardiovascular mortality in patients assigned to adaptive servo-ventilation (ASV) versus guideline-based medical treatment. To better understand the physiological underpinnings of this clinical outcome, we employ an integrative computer model to simulate congestive heart failure with Cheyne-Stokes respiration (CHF-CSR) in subjects with a broad spectrum of underlying pathogenetic mechanisms, as well as to determine the in silico changes in cardiopulmonary and autonomic physiology resulting from ASV. Our simulation results demonstrate that while the elimination of CSR through ASV can partially restore cardiorespiratory and autonomic physiology toward normality in the vast majority of CHF phenotypes, the degree of restoration can be highly variable, depending on the combination of CHF mechanisms in play.

A 30-Minute Spontaneous Breathing Trial Misses Many Children Who Go On to Fail a 120-Minute Spontaneous Breathing Trial.

Background: The optimal length of spontaneous breathing trials (SBTs) in children is unknown.

Research Questions: What are the most common reasons for SBT failure in children, and when do they occur? Can clinical parameters at the 30-min mark of a 120-min SBT predict outcome?

Study Design And Methods: We performed a secondary analysis of a clinical trial in pediatric ARDS, in which 2-h SBTs are conducted daily. SBT failure is based on objective criteria, including esophageal manometry for effort of breathing, categorized as passage, early failure (≤ 30 min), or late failure (30-120 min).

Vasoconstriction Response to Mental Stress in Sickle Cell Disease: The Role of the Cardiac and Vascular Baroreflexes.

Recent studies have shown that individuals with sickle cell disease (SCD) exhibit greater vasoconstriction responses to physical autonomic stressors, such as heat pain and cold pain than normal individuals, but this is not the case for mental stress (MTS). We sought to determine whether this anomalous finding for MTS is related to inter-group differences in baseline cardiac and vascular autonomic function. Fifteen subjects with SCD and 15 healthy volunteers participated in three MTS tasks: N-back, Stroop, and pain anticipation (PA).

Identifying elevated risk for future pain crises in sickle-cell disease using photoplethysmogram patterns measured during sleep: A machine learning approach.

Transient increases in peripheral vasoconstriction frequently occur in obstructive sleep apnea and periodic leg movement disorder, both of which are common in sickle cell disease (SCD). These events reduce microvascular blood flow and increase the likelihood of triggering painful vaso-occlusive crises (VOC) that are the hallmark of SCD. We recently reported a significant association between the magnitude of vasoconstriction, inferred from the finger photoplethysmogram (PPG) during sleep, and the frequency of future VOC in 212 children with SCD.

Loss of alpha-globin genes in human subjects is associated with improved nitric oxide-mediated vascular perfusion.

Alpha thalassemia is a hemoglobinopathy due to decreased production of the α-globin protein from loss of up to four α-globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co-inherit the loss of one or two α-globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α-globin gene deletions affect sickle red cell deformability, the α-globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction.

Nocturnal peripheral vasoconstriction predicts the frequency of severe acute pain episodes in children with sickle cell disease.

The basic model of SCD physiology states that vaso-occlusion occurs when hemoglobin S-containing red blood cells (RBC) undergo sickling before they escape the capillary into a larger vessel. We have shown that mental stress, pain and cold, and events reported by patients to trigger SCD vaso-occlusive crisis (VOC), cause rapid and significant decrease in blood flow, reducing the likelihood that RBC could transit the microvasculature before sickling occurs. However, the critical link between decrease in microvascular blood flow and the incidence of future sickle VOC has never been established experimentally in humans.

Effects of Ventilation-Perfusion Mismatch on Severity of Obstructive Sleep Apnea: A Modeling Study.

Plant gain quantifies the extent and rapidity with which arterial blood gases change following hypopneic or hyperpneic events. High plant gain, acting in concert with a highly collapsible upper airway and low arousal threshold, may contribute significantly towards increasing the severity of obstructive sleep apnea (OSA), even when controller gain is low. Elevated plant gain may be a manifestation of abnormal gas exchange resulting from ventilation-perfusion mismatch in the lungs.

Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups - revisiting this controversial concept after 16 years of additional evidence.

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD.

High Breath-by-Breath Variability Is Associated With Extubation Failure in Children.

Objectives: Extubation failure is multifactorial, and most tools to assess extubation readiness only evaluate snapshots of patient physiology. Understanding variability in respiratory variables may provide additional information to inform extubation readiness assessments.

Design: Secondary analysis of prospectively collected physiologic data of children just prior to extubation during a spontaneous breathing trial.

Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease.

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction.

Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain.

Phenotype of ventilatory control in children with moderate to severe persistent asthma and obstructive sleep apnea.

Study Objectives: To examine the role of ventilatory control in asthmatic children with obstructive sleep apnea (OSA) and the relationships between measures of ventilatory control, OSA severity, and pulmonary function.

Methods: Five- to 18-year-old children with persistent asthma and nightly snoring were enrolled in the study. Children had physical examination, pulmonary function test, and polysomnography.

Respiratory modulation of peripheral vasoconstriction: a modeling perspective.

Although respiratory sinus arrhythmia and blood pressure variability have been investigated extensively, there have been far fewer studies of the respiratory modulation of peripheral blood flow in humans. Existing studies have been based primarily on noninvasive measurements using digit photoplethysmography and laser-Doppler flowmetry. The cumulative knowledge derived from these studies suggests that respiration can contribute to fluctuations in peripheral blood flow and volume through a combination of mechanical, hemodynamic, and neural mechanisms.

Sickle Cell Disease Subjects Have a Distinct Abnormal Autonomic Phenotype Characterized by Peripheral Vasoconstriction With Blunted Cardiac Response to Head-Up Tilt.

In sickle cell disease (SCD), prolonged capillary transit times, resulting from reduced peripheral blood flow, increase the likelihood of rigid red cells entrapment in the microvasculature, predisposing to vaso-occlusive crisis. Since changes in peripheral flow are mediated by the autonomic nervous system (ANS), we tested the hypothesis that the cardiac and peripheral vascular responses to head-up tilt (HUT) are abnormal in SCD. Heart rate, respiration, non-invasive continuous blood pressure and finger photoplethysmogram (PPG) were monitored before, during, and after HUT in SCD, anemic controls and healthy subjects.

Mental stress causes vasoconstriction in subjects with sickle cell disease and in normal controls.

Vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD) and occurs when deoxygenated sickled red blood cells occlude the microvasculature. Any stimulus, such as mental stress, which decreases microvascular blood flow will increase the likelihood of red cell entrapment resulting in local vaso-occlusion and progression to VOC. Neurally mediated vasoconstriction might be the physiological link between crisis triggers and vaso-occlusion.

The effect of adenotonsillectomy on ventilatory control in children with obstructive sleep apnea.

Study Objectives: The contribution of ventilatory control to the pathogenesis of obstructive sleep apnea (OSA) in children and the effect of adenotonsillectomy are unknown. We aimed to examine the difference in ventilatory control between children with OSA and those without OSA. We also examined the effect of adenotonsillectomy on parameters of ventilatory control.

Quantifying ventilatory control stability from spontaneous sigh responses during sleep: a comparison of two approaches.

Rationale: Ventilatory control instability is an important factor contributing to the pathogenesis of periodic breathing (PB) and other forms of sleep-related breathing disorders (SRBD). The development of tools for the quantification of such instabilities from non-invasive respiratory measurements during sleep could be useful to clinicians in identifying subjects that are at risk of developing SRBD.

Objectives: To present and compare two different mathematical modeling approaches that allow the quantification of ventilatory control stability from the ventilatory responses to spontaneous sighs.

Abnormalities in autonomic function in obese boys at-risk for insulin resistance and obstructive sleep apnea.

Study Objectives: Current evidence in adults suggests that, independent of obesity, obstructive sleep apnea (OSA) can lead to autonomic dysfunction and impaired glucose metabolism, but these relationships are less clear in children. The purpose of this study was to investigate the associations among OSA, glucose metabolism, and daytime autonomic function in obese pediatric subjects.

Methods: Twenty-three obese boys participated in: overnight polysomnography; a frequently sampled intravenous glucose tolerance test; and recordings of spontaneous cardiorespiratory data in both the supine (baseline) and standing (sympathetic stimulus) postures.

Upper Airway Narrowing during Central Apnea in Obese Adolescents.

Rationale: The use of real-time magnetic resonance imaging (MRI) for the evaluation during sleep-related respiratory events can lead to better understanding of airway dynamics.

Objectives: To investigate the dynamic anatomy of the upper airway during central apnea.

Methods: The study included obese adolescents who snore and were otherwise healthy.

Autonomic nervous system involvement in sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder of hemoglobin producing hemoglobin-S (HbS) and resulting in recurrent severe episodes of pain, organ damage and premature death due to vaso- occlusion. Deoxy HbS polymerizes, causing red cells to become rigid and lodge in the microvasculature if they do not escape into larger vessels before this transformation occurs. The mechanism that triggers this transition from steady state to vaso-occlusive crisis (VOC) is not known.