biosensors Review Sources of Inaccuracy in Photoplethysmography for Continuous Cardiovascular Monitoring Jesse Fine 1, Kimberly L. Branan 1, Andres J. Rodriguez 2, Tananant Boonya-ananta 2, Ajmal 2, Jessica C. Ramella-Roman 2,3, Michael J. McShane 1,4,5,* and Gerard L. Coté 1,5,* 1 Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA; jfi[email protected] (J.F.); [email protected] (K.L.B.) 2 Department of Biomedical Engineering, Florida International University, Miami, FL 33174, USA; arodr829@fiu.edu (A.J.R.); tboon007@fiu.edu (T.B.-a.); aajma003@fiu.edu (A.); jramella@fiu.edu (J.C.R.-R.) 3 Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA 4 Department of Materials Science and Engineering, Texas A&M University, College Station, TX 77843, USA 5 Center for Remote Health Technologies and Systems, Texas A&M Engineering Experimentation Station, Texas A&M University, College Station, TX 77843, USA * Correspondence: [email protected] (M.J.M.); [email protected] (G.L.C.); Tel.: +1-979-845-7941 (M.J.M.); +1-979-458-6082 (G.L.C.) Abstract: Photoplethysmography (PPG) is a low-cost, noninvasive optical technique that uses change in light transmission with changes in blood volume within tissue to provide information for cardiovascular health and fitness. As remote health and wearable medical devices become more prevalent, PPG devices are being developed as part of wearable systems to monitor parameters such as heart rate (HR) that do not require complex analysis of the PPG waveform. However, complex analyses of the PPG waveform yield valuable clinical information, such as: blood pressure, respiratory information, sympathetic nervous system activity, and heart rate variability. Systems aiming to derive such complex parameters do not always account for realistic sources of noise, as testing is performed Citation: Fine, J.; Branan, K.L.; within controlled parameter spaces. A wearable monitoring tool to be used beyond fitness and heart Rodriguez, A.J.; Boonya-ananta, T.; rate must account for noise sources originating from individual patient variations (e.g., skin tone, Ajmal; Ramella-Roman, J.C.; obesity, age, and gender), physiology (e.g., respiration, venous pulsation, body site of measurement, McShane, M.J.; Coté, G.L. Sources of and body temperature), and external perturbations of the device itself (e.g., motion artifact, ambient Inaccuracy in Photoplethysmography light, and applied pressure to the skin). Here, we present a comprehensive review of the literature for Continuous Cardiovascular that aims to summarize these noise sources for future PPG device development for use in health Monitoring. Biosensors 2021, 11, 126. https://doi.org/10.3390/bios11040126 monitoring. Received: 8 March 2021 Keywords: photoplethysmography; cardiovascular disease; remote health Accepted: 9 April 2021 Published: 16 April 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Remote and continuous/intermittent monitoring (RCIM) has proven to be a promising published maps and institutional affil- route to deliver preventative care by reducing both the death rate and burdens placed on the iations. healthcare system [1–3]. One emerging RCIM technique frequently being used to monitor wellness is photoplethysmography (PPG). PPG works by illuminating the skin (commonly the finger, wrist, forearm, or ear) with light and collecting the transmitted or reflected light with a nearby detector. The collected light varies in intensity and has a pulsatile Copyright: © 2021 by the authors. component, often called the AC component, and a quasi-DC component. The variation Licensee MDPI, Basel, Switzerland. in the quasi-DC component is due to many factors: the optical properties of the tissue, This article is an open access article average blood volume, respiration, vasomotor activity, vasoconstrictor waves, Traube distributed under the terms and Hering Meyer waves, and thermoregulation [4–14]. The common pulsatile (“AC”), change conditions of the Creative Commons in the PPG is usually the variation associated with arterial blood volume. As the systolic Attribution (CC BY) license (https:// and diastolic pulse travel through an artery or arteriole, the properties of the pulse itself and creativecommons.org/licenses/by/ the compliance of the vessel lead to a change in vessel diameter and consequently a change 4.0/). Biosensors 2021, 11, 126. https://doi.org/10.3390/bios11040126 https://www.mdpi.com/journal/biosensors Biosensors 2021, 11, x FOR PEER REVIEW 2 of 36 Biosensors 2021, 11, 126 2 of 36 the compliance of the vessel lead to a change in vessel diameter and consequently a changein blood in blood volume. volume. This This correlates correlates with with a change a change in lightin light detected detected by by a photodiodea photodiode after afterillumination illumination and and hence hence a a change change in in the the voltage voltage or or current current generated generated by by the the photodetector. photode- tector.Changes Changes in erythrocyte in erythrocyte orientation orientation can also can lead also to lead changes to changes in optical in transmittance, optical transmit- further tance,modifying further modifying light detected light by detected a photodiode by a photodiode as a function as a of function blood volume of blood [15 volume]. Over an [15].entire Over cardiacan entire cycle, cardiac if the cycle, quasi-DC if the quasi- baselineDC lightbaseline signal light from signal the from other the tissue other parameters tissue parametersis removed, is removed, this leads this to leads the to AC the PPG AC waveform,PPG waveform, which which is attributed is attributed primarily primarily to the to thecardiac cardiac pulse. pulse. This This pulse pulse is often is often inverted inverted and and displayed displayed as seen as seen in Figure in Figure1a . In 1a. addition In additionto the to possibility the possibility of gathering of gathering clinical clinic informational information from from the the PPG PPG waveform waveform itself, itself, some somehave have used used its its derivatives derivatives to to gather gather information information includingincluding the firstfirst derivative known known as as thethe velocity velocity plethysmograph plethysmograph (VPG, (VPG, Figure Figure 1b)1b) and and the the second second derivative derivative known known as asthe the secondsecond derivative derivative photoplethysmograph photoplethysmograph or or acceleration acceleration plethysmographplethysmograph (SDPPG (SDPPG or or APG, APG,Figure Figure1c) 1c) [16 ].[16]. FigureFigure 1. (a 1.) Photoplethysmography(a) Photoplethysmography (PPG) (PPG) waveform: waveform: 1. systolic 1. systolic peak; peak; 2. dicrotic 2. dicrotic notch; notch; 3. dias- 3. diastolic tolicpeak; peak;4. 4. slopeslope transit time; 5. heart heart rate; rate; 6. 6. area area under under systo systoliclic waveform; waveform; 7. 7.area area under under dias- diastolic tolicwaveform; waveform;( (bb)) firstfirst derivative,derivative, velocityvelocity plethysmograph (VPG): (VPG): 8. 8. max max slope slope in in systole; systole; 9. 9. end end of of systolic peak; 10. Start of dicrotic notch; 11. max slope in diastole; (c) second derivative, second systolic peak; 10. Start of dicrotic notch; 11. max slope in diastole; (c) second derivative, second derivative photoplethysmograph or acceleration plethysmograph (SDPPG/APG): 12. a-point; 13. derivative photoplethysmograph or acceleration plethysmograph (SDPPG/APG): 12. a-point; 13. b- b-point; 14. c-point; 15. d-point; 16. e-point. Created with BioRender.com. point; 14. c-point; 15. d-point; 16. e-point. Created with BioRender.com. Beyond fitness and heart rate monitoring, the primary medical use of the PPG has Beyond fitness and heart rate monitoring, the primary medical use of the PPG has been beenfocused focused on on obtaining obtaining information information about about the the cardiovascular cardiovascular system system towards towards cardiovascular cardio- vasculardisease disease (CVD) (CVD) diagnosis diagnosis and treatment and treatment [17,18]. [17,18]. CVD is CVD a class is ofa chronicclass of conditionschronic condi- and is a tionsgeneral and is term a general for those term diseases for those that diseases affect the that heart affect or blood the vessels,heart or and blood include vessels, (but and are not includelimited (but to): are coronary not limited artery to): disease, coronary cardiomyopathy, artery disease, heart cardiomyopathy, failure, arrhythmia, heart myocardialfailure, arrhythmia,infarction, myocardial and peripheral infarction, artery and disease peripheral [19]. CVD artery is oftendisease associated [19]. 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