BEst (Biomarker Estimation): Health Biomarker Estimation Non-invasively and Ubiquitously

This dissertation focuses on the non-invasive assessment of blood-hemoglobin levels. The primary goal of this research is to investigate a reliable, affordable, and user-friendly point-of-care solution for hemoglobin-level determination using fingertip videos captured by a smartphone. I evaluated videos obtained from five patient groups, three from the United States and two from Bangladesh, under two sets of lighting conditions. In the last group, based on human tissue optical transmission modeling data, I used near-infrared light-emitting diode sources of three wavelengths. I developed novel image processing techniques for fingertip video analysis to estimate hemoglobin levels. I studied video images creating image histogram and subdividing each image into multiple blocks. I determined the region of interest in a video and created photoplethysmogram signals. I created features from image histograms and PPG signals. I used the Partial Least Squares Regression and Support Vector Machine Regression tools to analyze input features and to build hemoglobin prediction models. Using data from the last and largest group of patients studied, I was able to develop a model with a strong linear correlation between estimated and clinically-measured hemoglobin levels. With further data and methodological refinements, the approach I have developed may be able to define a clinically accurate public health applicable tool for hemoglobin level and other blood constituent assessment

The Challenges and Pitfalls of Detecting Sleep Hypopnea Using a Wearable Optical Sensor: Comparative Study.

BACKGROUND Obstructive sleep apnea (OSA) is the most prevalent respiratory sleep disorder occurring in 9% to 38% of the general population. About 90% of patients with suspected OSA remain undiagnosed due to the lack of sleep laboratories or specialists and the high cost of gold-standard in-lab polysomnography diagnosis, leading to a decreased quality of life and increased health care burden in cardio- and cerebrovascular diseases. Wearable sleep trackers like smartwatches and armbands are booming, creating a hope for cost-efficient at-home OSA diagnosis and assessment of treatment (eg, continuous positive airway pressure [CPAP] therapy) effectiveness. However, such wearables are currently still not available and cannot be used to detect sleep hypopnea. Sleep hypopnea is defined by ≥30% drop in breathing and an at least 3% drop in peripheral capillary oxygen saturation (Spo2) measured at the fingertip. Whether the conventional measures of oxygen desaturation (OD) at the fingertip and at the arm or wrist are identical is essentially unknown. OBJECTIVE We aimed to compare event-by-event arm OD (arm_OD) with fingertip OD (finger_OD) in sleep hypopneas during both naïve sleep and CPAP therapy. METHODS Thirty patients with OSA underwent an incremental, stepwise CPAP titration protocol during all-night in-lab video-polysomnography monitoring (ie, 1-h baseline sleep without CPAP followed by stepwise increments of 1 cmH2O pressure per hour starting from 5 to 8 cmH2O depending on the individual). Arm_OD of the left biceps muscle and finger_OD of the left index fingertip in sleep hypopneas were simultaneously measured by frequency-domain near-infrared spectroscopy and video-polysomnography photoplethysmography, respectively. Bland-Altman plots were used to illustrate the agreements between arm_OD and finger_OD during baseline sleep and under CPAP. We used t tests to determine whether these measurements significantly differed. RESULTS In total, 534 obstructive apneas and 2185 hypopneas were recorded. Of the 2185 hypopneas, 668 (30.57%) were collected during baseline sleep and 1517 (69.43%), during CPAP sleep. The mean difference between finger_OD and arm_OD was 2.86% (95% CI 2.67%-3.06%, t667=28.28; P<.001; 95% limits of agreement [LoA] -2.27%, 8.00%) during baseline sleep and 1.83% (95% CI 1.72%-1.94%, t1516=31.99; P<.001; 95% LoA -2.54%, 6.19%) during CPAP. Using the standard criterion of 3% saturation drop, arm_OD only recognized 16.32% (109/668) and 14.90% (226/1517) of hypopneas at baseline and during CPAP, respectively. CONCLUSIONS arm_OD is 2% to 3% lower than standard finger_OD in sleep hypopnea, probably because the measured arm_OD originates physiologically from arterioles, venules, and capillaries; thus, the venous blood adversely affects its value. Our findings demonstrate that the standard criterion of ≥3% OD drop at the arm or wrist is not suitable to define hypopnea because it could provide large false-negative results in diagnosing OSA and assessing CPAP treatment effectiveness

In vivo non-invasive monitoring of optically resonant metal nanoparticles using multi-wavelength photoplethysmography

Nanotechnology has recently emerged as a powerful modality in many biomedical applications. In particular, several classes of nanoparticles have been employed as cancer therapy and imaging contrast agents. These particles can have architecture of varying complexity, depending on their specific application. These complex architectures are achieved by various chemical techniques usually performed in specific sequences to add complexity and functionality. One such class of nanoparticle, used in tumor treatment and as contrast agents in several optical imaging techniques, is the plasmon resonant metal nanoparticle. The most common metal used for these particles is gold because of its biocompatibility, lack of cellular toxicity, and simple surface chemistry. These particles have specific optical properties in the near infrared spectrum making them ideal for modern cancer therapy and optical imaging. Two examples of these particles are gold nanoshells and gold nanorods, both of which are highly absorptive and scattering at near infrared wavelengths. It is for this reason that they are often employed in photo thermal ablation of tumors using near infrared light. In this type of tumor treatment, the particles are injected intravenously and accumulate in the tumor. After accumulation, a near infrared laser is used to heat the particles and destroy the tumor. These gold nanoparticles must be modified with biocompatible stealthing compounds before they can be injected. This is because of the high efficiency of the body\u27s reticuloendotheial system, which will quickly eliminate materials foreign through cellular phagocytosis. Although techniques for quality control in manufacturing these nanoparticles are used to confirm proper surface modification, their in vivo behavior is very difficult to predict. It is for this reason that real time feedback in nanoparticle therapy is an urgent need and will greatly improve its efficacy. This dissertation reports the development of a non-invasive optical system capable of reporting the in vivo vascular concentration of these nanoparticles in near real time. The device, termed the pulse photometer, utilizes a technique similar to that used in pulse oximetry. This technique is photoplethysmography, which has many medical applications. One of these is determining the optical characteristics of pulsatile arterial blood, which are affected after the injection of these optically resonant particles. Several prototypes of this are presented in this dissertation. The culmination of this work is the prototype III pulse photometer capable of concurrent nanoparticle monitoring and oximetry. Final testing of this prototype revealed its ability to accurately determine the vascular optical density of gold nanorods compared to ex vivo spectrophotometry, a technique also verified in this dissertation, by statistical Bland-Altman analysis

A novel, non-invasive, optical device for the measurement of total haemoglobin and stroke volume, and for the identification of fluid responsiveness – initial clinical evaluation

Haemoglobin is a molecule present in red blood cells and is essential for adequate oxygen delivery to tissues. It is measured frequently in many clinical situations, particularly intraoperatively. Until recently, it was only possible to measure haemoglobin through blood testing which is an invasive process and requires some time to process. Devices have been developed in the last number of years to minimise both the invasiveness and time needed to measure haemoglobin. More recently, devices are available that provide instant or continuous results without requiring blood samples but these have not been universally accepted into clinical practice. Stroke volume is the amount of blood ejected from the heart at each heartbeat, and is one of the determinants of cardiac output (which is also responsible for ensuring adequate tissue oxygen delivery). It varies across many clinical states, particularly following major haemorrhage or reduced cardiac function. The analysis of variations in stroke volume during the respiratory cycle (i.e. between the end of a complete exhalation and the end of the following complete exhalation) has been shown to predict when a patient’s stroke volume could be improved by administering intravenous fluid. Successfully identifying such ‘responders’ can lead to earlier appropriate treatment, and also avoid over-treatment. However, at present the most reliable methods of measuring stoke volume or predicting fluid responsiveness involve the use of invasive devices which have the potential to be harmful. A novel device has been developed which uses the absorbance of red and near-infrared light across a finger tip as the basis for the measurement of both haemoglobin and stroke volume, along with the prediction of fluid responsiveness. This is non-invasive and would allow for the continuous measurement of these physiological parameters, with potential for more efficient and timely treatment.This thesis presents the first clinical evaluation of the two functions of this novel device across three studies. The first study investigated the measurement of haemoglobin by this device across twenty five patients undergoing heart surgery who each underwent four samples. The second study looked into the measurement of haemoglobin in one hundred pregnant women during their twenty- week antenatal clinic visit. In both studies, the results from the device were compared with the standard laboratory method of measurement. The third study investigated the device’s ability to measure stoke volume and to predict fluid responsiveness in twenty patients undergoing heart surgery. The results of these studies showed that the device is currently not suitable for use in clinical practice as a replacement for the more established methods of measurement one each case. Some explanation is offered regarding the poor results

Use of near-infrared systems for investigations of hemodynamics in human in vivo bone tissue: a systematic review

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.A range of technologies using near infrared (NIR) light have shown promise at providing real time measurements of hemodynamic markers in bone tissue in vivo, an exciting prospect given existing difficulties in measuring hemodynamics in bone tissue. This systematic review aimed to evaluate the evidence for this potential use of NIR systems, establishing their potential as a research tool in this field. Major electronic databases including MEDLINE and EMBASE were searched using pre‐planned search strategies with broad scope for any in vivo use of NIR technologies in human bone tissue. Following identification of studies by title and abstract screening, full text inclusion was determined by double blind assessment using predefined criteria. Full text studies for inclusion were data extracted using a predesigned proforma and quality assessed. Narrative synthesis was appropriate given the wide heterogeneity of included studies. Eighty‐eight full text studies fulfilled the inclusion criteria, 57 addressing laser Doppler flowmetry (56 intra‐operatively), 21 near infrared spectroscopy, and 10 photoplethysmography. The heterogeneity of the methodologies included differing hemodynamic markers, measurement protocols, anatomical locations, and research applications, making meaningful direct comparisons impossible. Further, studies were often limited by small sample sizes with potential selection biases, detection biases, and wide variability in results between participants. Despite promising potential in the use of NIR light to interrogate bone circulation, the application of NIR systems in bone requires rigorous assessment of the reproducibility of potential hemodynamic markers and further validation of these markers against alternative physiologically relevant reference standards.This systematic review was supported by the College of Radiographers Industry Partnership Scheme (CORIPS) Doctoral Fellowship Grant (Applicant 003). The CORIPS are providing financial support but have no input into the design, performance or analysis of this systematic review. WDS, FC and CT would like to acknowledge the NIHR Exeter Clinical Research Facility and the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR Exeter Clinical Research Facility, the NHS, the NIHR or the Department of Health in England

Opto-physiological modeling applied to photoplethysmographic cardiovascular assessment

This paper presents opto-physiological (OP) modeling and its application in cardiovascular assessment techniques based on photoplethysmography (PPG). Existing contact point measurement techniques, i.e., pulse oximetry probes, are compared with the next generation noncontact and imaging implementations, i.e., non-contact reflection and camera-based PPG. The further development of effective physiological monitoring techniques relies on novel approaches to OP modeling that can better inform the design and development of sensing hardware and applicable signal processing procedures. With the help of finite-element optical simulation, fundamental research into OP modeling of photoplethysmography is being exploited towards the development of engineering solutions for practical biomedical systems. This paper reviews a body of research comprising two OP models that have led to significant progress in the design of transmission mode pulse oximetry probes, and approaches to 3D blood perfusion mapping for the interpretation of cardiovascular performance

Wireless monitoring of liver hemodynamics in vivo

Liver transplants have their highest technical failure rate in the first two weeks following surgery. Currently, there are limited devices for continuous, real-time monitoring of the graft. In this work, a three wavelengths system is presented that combines near-infrared spectroscopy and photoplethysmography with a processing method that can uniquely measure and separate the venous and arterial oxygen contributions. This strategy allows for the quantification of tissue oxygen consumption used to study hepatic metabolic activity and to relate it to tissue stress. The sensor is battery operated and communicates wirelessly with a data acquisition computer which provides the possibility of implantation provided sufficient miniaturization. In two in vivo porcine studies, the sensor tracked perfusion changes in hepatic tissue during vascular occlusions with a root mean square error (RMSE) of 0.135 mL/min/g of tissue. We show the possibility of using the pulsatile wave to measure the arterial oxygen saturation similar to pulse oximetry. The signal is also used to extract the venous oxygen saturation from the direct current (DC) levels. Arterial and venous oxygen saturation changes were measured with an RMSE of 2.19% and 1.39% respectively when no vascular occlusions were induced. This error increased to 2.82% and 3.83% when vascular occlusions were induced during hypoxia. These errors are similar to the resolution of a commercial oximetry catheter used as a reference. This work is the first realization of a wireless optical sensor for continuous monitoring of hepatic hemodynamics. © 2014 Akl et al

A calibration method for smartphone camera photophlethysmography

Smartphone camera photoplethysmography (cPPG) enables non-invasive pulse oximetry and hemoglobin concentration measurements. However, the aesthetic-driven non-linearity in default image capture and preprocessing pipelines poses challenges for consistency and transferability of cPPG across devices. This work identifies two key parameters—tone mapping and sensor threshold—that significantly impact cPPG measurements. We propose a novel calibration method to linearize camera measurements, thus enhancing consistency and transferability of cPPG across devices. A benchtop calibration system is also presented, leveraging a microcontroller and LED setup to characterize these parameters for each phone model. Our validation studies demonstrate that, with appropriate calibration and camera settings, cPPG applications can achieve 74% higher accuracy than with default settings. Moreover, our calibration method proves effective across different smartphone models (N=4), and calibrations performed on one phone can be applied to other smartphones of the same model (N=6), enhancing consistency and scalability of cPPG applications

Near Infrared Spectroscopy is not a Surrogate of Venous Occlusion Plethysmography to Assess Microvascular Resting Blood Flow and Function

International Journal of Exercise Science 15(2): 1616-1626, 2022. Near-infrared spectroscopy (NIRS) is a non-invasive technique that measures tissue perfusion using red blood cells oxygen saturation and venous occlusion plethysmography (VOP) is the gold standard to assess microvascular blood flow and function. The purpose of this study was to determine if NIRS can surrogate the microvascular blood flow assessment after an ischemic challenge obtained via VOP. Twenty apparently healthy subjects (10 males and 10 females), aged 18 to 35 years, were recruited for this single session study. NIRS probes were placed 40mm apart along the epicondylar muscles on the right forearm and on the tibialis anterior on the right lower leg, while VOP strain gauges were placed on the largest circumference on both right forearm and calf. Blood flow via VOP and NIRS variables (hemoglobin saturation (SO2), oxygenated hemoglobin (HbO2), and deoxyhemoglobin (HHb) slopes) were assessed before and after 5-min ischemic challenge. Person’s correlations and intra-class correlations (ICC2k) were conducted for each of the NIRS variables vs VOP. There were moderate associations between of SO2 and HbO2 slopes and VOP (r = 0.59, p \u3c 0.01 and r = 0.53, p \u3c 0.05, respectively) at the lower body during resting conditions. There was a poor agreement between NIRS SO2 and VOP at the resting condition in the lower body (ICC2k = 0.45). There were no other associations between any of the other NIRS variables and VOP of the lower and upper body at resting or post-ischemic conditions. In conclusion, NIRS cannot surrogate VOP for measurements of microvascular blood flow at resting or post-ischemic conditions