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An interactive computer system for studying human mucociliary clearance
OOIO-4825/79/04014097
Compur. Biol. Med. Vol. 9, pp. 97-105. 0 Pergamon Press Ltd. 1979. Printed in Great Britain.
w2.co/o
AN INTERACTIVE COMPUTER SYSTEM FOR STUDYING HUMAN MUCOCILIARY CLEARANCE PAUL G. BASSETT Department of Computer Science, York University, Toronto, Ontario, Canada
and JOHN W. WONG and NORMANASPIN The Research Institute, Hospital for Sick Children, Toronto, Canada M5G 1X8 and The Departments of Medical Biophysics and Pediatrics, University of Toronto, Canada (Received 2 May 1978; received for publication 13 September 1978)
Abstract - This paper describes the incorporation of a computer for interactive data collection and analysis into the study of mucous clearance in the human trachea. The success of this system greatly improves the efficiency of data analysis and reduces significantly the possibility of human error that existed in manual operation. Mucociliary clearance framing Peak analysis
Interactive computer system
Structured-FORTRAN
Graphics
Data-
INTRODUCTION The “mucociliary escalator” is one of the major mechanisms by which the lung removes inhaled pollutants. In the lung, cilia are found in the conducting airways, from the trachea (25 mm in dia.), down to the level of the terminal bronchioles (0.65mm in dia.) [l]. These hair-like projections, 5-7 pm in length, cover 3060% of this total surface area, and oscillate in a coordinated whipping fashion so as to sweep along an overlying layer of mucus. The mucus is transported by this ciliary activity from the distal airways up through the trachea, past the larynx, where upon it is swallowed. In this manner, inhaled pollutants that are deposited on the mucous blanket in the airways are removed from the lung. In the past, mucociliary activity has been studied in man by measuring with external scintillation detectors, the half time of disappearance of inhaled radioactive particles from the lung [2]. Such investigations do not provide information on the rates of mucous movement in individual airways. Two methods have been developed to measure such rates in the trachea. One method utilizes a fibre-optic bronchoscope to measure the movement of small teflon discs deposited on top of the tracheal mucus blanket [3]. Since the procedure was invasive, a recent modification has been made whereby fluoroscopy replaced bronchoscopy as the method of detection of the discs [4]. The other method, developed in this laboratory, uses a non-invasive radioisotope imaging technique [5]. The procedure is described below and presented schematically in Fig. 1. The subject takes a dozen breathes from a spirometer system which injects into the latter portion of each breath a dense aerosol mist containing microspheres of albumin labelled with 99mTc. The radioactive microspheres are preferentially deposited by impaction on the bifurcations of the major airways as local aggregations or boluses. These boluses are subsequently cleared by the mucociliary escalator. Using a scintillation camera, many boluses can be observed to move up the trachea in the few hours following deposition of the radioactive microspheres. A rectangular “region of interest” is centered electronically over the image of the trachea. In sequential time intervals or frames, the activity along the tracheal region of interest is displayed on the CRT of a multichannel analyser as a counts vs distance histogram. In this mode of data presentation, a bolus of radioactivity within the trachea appears as a peak in each frame display. By estimating from each film record, the distance of a 97
98
PAULG. BASSETT, JOHNW. WONGand NORMANASPIN SCINTILLATION
IMAGE
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OF INTEREST
: : : : :
i
’
!
:
a SUBJECT
POLAROID CAMERA
Fig. 1. A schematic presentation of data collection with Polaroid camera in a study of mucous clearance.
peak from the carina at the base of the trachea, and by repeating this measurement over a large number of frames, the rate of bolus movement up the trachea is determined. This technique has been used to measure mucous transport rates in normal subjects [5] and in patients with cystic fibrosis (CF) where mucous secretion and its clearance are considered to be abnormal [6]. It is apparent that the above method of data analysis requires laborious manual determination of the position of a bolus on a large number of Polaroid films. For this reason, the determination of peak position tends to become subjective and prone to error. Moreover, the time required for this analysis is the limiting factor in the number of studies which can be performed. This paper describes an interactive digital computer system for data recording and analysis which overcomes the drawbacks that are inherent in the procedure described above. HARDWARE
AND SOFTWARE
ENVIRONMENT
The physical configuration of the equipment and the flow of data between the components is described as follows : Count data from the region of interest (7.5 cm x 15 cm) is temporarily stored in a buffer memory device (Northern Scientific Inc., NS-625 and NS-630) of the scintillation camera. This data is stored in 64 channels or resolution intervals and is displayed on the CRT of the buffer memory as a histogram of counts vs channel number. The contents of the buffer memory are then transmitted to a time-shared IBM 1800 process control computer through 16 digital input lines of a 1000 ft cable. A computer program which allows for operator intervention in data collection and analysis is filed on a system disc and study data are stored on a removable disc. For direct operator interaction with data processing, a computer connected graphic CRT-keyboard terminal is located beside the scintillation camera. This keyboard is equipped with software implemented, special function keys. The CRT is a Ramtek GX-100 with 512 lines x 256 element resolution which displays data as a histogram of counts vs tracheal distance. Upon completion of a study, a data review mode is provided by the system. A Versa& Matrix Printer is available for copying the processed data from the terminal display. A complete printout of all analysed data can be obtained from the computer line-printer. Within the context of the above hardware environment the following is a brief description of the software environment in which the application programs were developed. The IBM 1800 is equipped with the Multi Programming Executive (MPX) operating system. A considerable amount of additional software has been added by the programming
Human mucociliary clearance
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staff. This additional support is sufficient to service up to lographic terminals each providing a unique selection of application programs. A graphic language processor or compiler has been implemented which permits a convenient declaration of interactive graphic displays and implements an interface so that the data coming from the terminal can relate directly to the real-time data base. Nestled within this context approximately 40 FORTRAN modules have been designed and implemented using the technique of structured programming. All programs including the MPX operating system and the graphics package are available on disc cartridges. Copies of the discs and the User Manual can be provided (upon request to the authors) to anyone having a similar configuration (including the GX-100 CRT’s). The system’s top level is structured as three modules which: (a) define a study; (b) capture, display, store and statistically analyse the data in real time under a priority interrupt scheme; (c) permit a post-study review of all the data captured and its analysis, with over-ride calculations to re-analyse and/or re-store statistical information about the study. Subsequent sections of this paper outline how these modules are used by the experimenter.
DESCRIPTION
OF STUDY
PROCEDURE
1. Study preparation At the start of a study, the “mucociliary clearance” program is invoked by a START key on the terminal and a disc is mounted for data collection. The system then requests preliminary study parameters as shown in the CRT display of Fig. 2. The subject’s name is entered for identification. The carina and larynx channel numbers in the region of interest are required to specify the fiducial registration points of the trachea. The mm-per-channel provides the current camera calibration and permits a linear conversion from channel numbers to tracheal distance, where the carina channel defines the origin. A time-out interval, or time between data frames is entered as an arbitrary time (usually 60 min) by which the system will terminate data collection if no further data is forthcoming. After entering these parameters, the program is readied for receiving data. To register the limits of the trachea for the system, the positions of the subject’s larynx and carina, as inferred from a chest radiograph of low magnification are first marked on the skin. The subject is then seated in front of the scintillation camera, with two radioactive point
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PAUL G. BASSETT,JOHN W. WONG
100
NORMAN ASPIN
and
sources placed over these markings. The subject is arranged to ensure that the scintillation images from the point sources fall into the region of interest. With the aid of the CRT display of the memory buffer, the larynx and carina channel numbers are determined as the maxima of the two peaks. Two lights are focussed on skin marks on the subject’s back which allows the subject to move away from the camera and to be quickly and accurately repositioned. Once this positioning information is obtained, the point sources are removed and the subject comes out of the seated position for inhalation of the radioactive particles. After deposition of radioactivity, the subject is realigned in his seated position and rigidly supported in front of the scintillation camera. A special function key (CAM) on the terminal keyboard is pressed to start elapsed time counting and data collection. 2. Data collection : time-partitioning
or framing
The time interval between data transmission from the buffer memory to the computer is preset by the operator but can be reset during the course of the study. This time interval or frame usually ranges between 30 and 120s~ and is adjusted to obtain optimal balance between counting statistics and rate of bolus movement. At the start of each frame, the memory buffer is cleared and scintillation counts are accumulated. At the end of each frame, an interrupt is received by the computer from the buffer memory device which initiates the transfer of the buffer contents to the CPU. Each transmission requires approximately 2 msec, during which no scintillation counts are stored. This data is converted into a counts vs tracheal distance histogram and is displayed on the terminal CRT screen upon which the operator can perform real-time data analysis. 3. Data display Figure 3 illustrates a frame display from the terminal screen. Frames are numbered sequentially in order to permit post-study paging (cf. data review). Since each frame results
MUCOCIL
IARY
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Fig. 3. A typical data display as seen on the terminal CRT showing a peak at the position of the larynx due to initially impacted radioactivity and a bolus-peak on its course up the trachea. Instructions are provided to aid the operator in real-time data analysis.
101
Human mucociliary clearance
from a relatively long data capture time interval, the elapsed time for a frame is registered as that of the mid-point of the actual time interval. When a bolus of radioactive particles is observed in a particular region of the trachea, it appears in the frame display as a count peak in the corresponding position along the tracheal axis (Fig. 3). There is usually a stationary accumulation ofcounts at the position of the larynx (L) due to impaction of the radioactivity during inhalation. Depending on the amount of radioactivity in the trachea and the choice of frame time, the range of counts during the study may vary by two orders of magnitude. The programs respond by automatically resealing the y-axis for each frame so that the quadrant is completely filled. This enables the user to judge each peak on a relative comparison basis using the maximum available resolution. The cursor field at the bottom of the frame display permits the entry of interactive instructions on the first line, and descriptive comments about the frame on the second line. Through the cursor field, the software design of the system enables the user in real time to locate and store positional information of the bolus-peaks observed in the tracheal distance. 4. Real time data analysis:
peak selection
When a peak appears in a frame (Fig. 3) the peak selection procedure provided by the program enables the system to keep track of the bolus both in time and tracheal position. Since an uneven background count level usually exists, and multiple peaks may be present, the decision as to what constitutes a peak must be made by the experimenter. In order to diminish most effectively the erroneous contribution due to background, a bolus is identified as a peak in the count-distance histogram above the base-line joining two local minima (Fig. 4). It must have a minimum full width half maximum (FWHM) of 1.60cm, which is the resolution of the detector to a 3mm point source of radioactivity. If this definition cannot be
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Fig. 4. A presentation ofa frame display analysed in real time. Two cursors, left and right are used for locating a bolus peak. Position and time data of this peak is stored by giving it a name, B, and pressing a STR function key. Its rate ofmovement up to this frame can be obtained by pressing a FIT function key. Additional comment regarding a frame display can also be stored in the comment field.
PAUL G. BASSETT,JOHNW. WONG and NORMANASPIN
102
satisfied due to a high background then arbitrarily the maximum counts in a peak must be at least two standard deviations above the highest local minimum. The terminal has no light pen for peak location purposes. However, a convenient alternative consists of two vertical moveable cursors, as illustrated in Fig. 4. These hairline cursors are initially superimposed in the first frame display (Fig. 3). A function key enables the user to manipulate either one cursor or the other. A small flag at the top indicates which cursor is currently in use. To move a cursor the user makes a coarse adjustment by entering the desired horizontal position (in mm) and pressing the JMP (jump) key. LFT (left) and RGT (right) fine adjustment keys move the active cursor incrementally from the current position to an adjacent observed tracheal count. For defining the limits of a peak in the display, these cursors are positioned over the two adjacent local minima (Fig. 4). For each peak isolated by the two cursors, the program calculates the mid-point, XM, as a weighted average as follows :
x
=i=l M
c
IC(i) - B(i) 1
i& I W
. X(i)
-
*
- W
(r - 1 2 2)
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where 1 and r are the corresponding left and right indicies of the two selected minima, C(i) is the observed count of the peak in the ith position, B(i) is the base-line ordinate in the ith position, X(i) is the distance of the ith position from the carina in mm. A vertical line is drawn through the peak at Xu to indicate its mid-point. In addition, the total counts above the base-line are displayed as shown in Fig. 4. This peak-picking procedure represents one major refinement over the manual approach. It offers a consistent, definitive method of locating the position of a bolus, thus eliminating the error prone method using Polaroid film. Having isolated a particular,peak, the operator types in a single letter name for bolus identification, such as B in Fig. 4, and stores it by depressing the STR function key. Upon receiving this store command, the system looks up the file for the particular bolus name, or creates one if this is a new bolus, and adds to the file a record of the elapsed time of the frame, and the X,,, of the peak. In doing so, the bolus name, and its counts are also added onto the counts versus distance distribution of the frame display. Such updating of the display provides the operator with identifying references during data review. If a bolus should split into two (or the reverse), the resultant boluses are given new letters so that separate transport rate statistics can be maintained. At any time during the study, the following statistics are calculated for any bolus by using the FIT function key: (1) The number of frames in which a particular bolus-peak were observed. (2) The rate of bolus transport based on the slope of the least-squares straight line fitted through the data points of the bolus. (3) The standard error of the rate. (4) The percentage error of the rate. (5) F-ratio, correlation coefficient and r-test as evaluations of the significance of the least square fit through the data points. (6) The standard error of the estimate of the position data. (7) The absolute value of the 95:/, confidence limits of the rate. ,However, only the transport rate of the particular bolus being fitted is shown on the display during the study (Fig. 4). This in-study bolus rate information enables the experimenter to optimize between frame time and counting statistics. The remaining information is available at the completion of the study (cf. data review, Table 1).
5. Data review
A typical study may encompass several hundred frames collected over 3-5 hr. Upon
Human mucociliary clearance
103
Table 1. Summary printout of a study from the computer line-printer
Bolus A B
c D E F
Rate (B) (mm/min) 3.53 3.17 2.25 3.00 1.18 2.03
Frames 29 26 22 19 22 14
R
F ratio 2646.072 8723.484 918.923 532.281 694.660 2384.476
PC E (B) 1.944 1.070 3.298 4.334 3.794 2.047
SE (B) 0.068 0.034 0.074 0.130 0.044 0.041
0.994 0.998 0.989 0.984 0.985 0.997
T-test 51.440 93.399 30.313 23.071 26.356 48.831
SEE 0.251 0.101 0.217 0.335 0.195 0.106
c 0.141 0.070 0.155 0.274 0.093 0.090
Bolus: Name ofa particular bolus. Frames : Number offrames in which a particular bolus was observed. Rate(B): Rate of movement of a bolus as calculated from the least-squares regression fit of all data points. SE (B): The standard error of the rate. PC E (B): The percentage error of the rate. F-Ratio, R (correlation coefficient), T-Test are standard evaluations of significance of the regression line. SEE: The standard error of the estimate of the position data. C: The absolute value of the 95u/, confidence limits of the rate.
completion of a study, a special frame “0” is displayed on the terminal (Fig. 5) summarizing the data which has been stored and analysed. Every selected peak is plotted on a time-displacement scattergram along with all regression lines that have been fitted. This global view of all the collected data represents a tremendous saving of time and of manual effort. It also permits the operator to quickly spot any obvious error made in real time, that in a local context is inconsistent with the overall evolutionary patterns in this display. In a data review mode provided by the system, the operator may page through the recorded frames in any sequence or order that he prefers. Corrections of erroneous choices, or addition of data missed during the study can be made. Upon completion of data review, all statistical calculations on the bolus files are updated and a final conclusive time-displacement scattergram is displayed, similar to that of Fig. 5. As mentioned before, hard copies of any
‘76
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Fig. 5. A typical time-displacement scattergram summarizing a)) data analysed during the study. This display is available upon completion of a study and can be updated in the data review mode. Bolus F in this particular display is a rename of bolus E as it underwent a change of rate.
104
PAUL G. BASSETT,
W. WONG and NORMANASPIN
frame displays can be obtained through a Versatec Matrix Printer, thus making the disc available for another study. In addition, a complete printout of all quantitative data collected and bolus statistics are produced by the computer line-printer. Table 1 shows the statistical information available from such a printout. CONCLUSION This paper describes an interactive computer-graphics system which has been used to increase the efficiency and objectivity in analysing data from a study, while reducing the amount of error induced by human effort. The operational simplicity of this radionuclide imaging-computer system for studying mucous clearance has facilitated investigations into a number of clinically interesting problems. For example we have studied the effect of gravity on the mucous transport rates of normal subjects and patients with cystic fibrosis [7). To undertake such studies using the manual approach to data analysis would be too lengthy, tedious, and error prone. Beyond the technical and clinical aspects of this work, we would like to emphasize that biomedical workers can and should expect to benefit from the growing maturity of the software profession. Techniques such as structured programming permit the timely development of reliable programs that provide friendly, convenient interfaces with naive users. Furthermore, hardware costs are now such that interactive techniques, until recently the preserve of well-endowed institutions, are readily available to most people with more modest research grants. Acknowledgements -The authors wish to thank staff of the Department of Clinical Computer Systems, Hospital for Sick Children for their cooperation and Mr. K. Steimann for technical assistance. This work was supported by a grant from the Medical Research Council of Canada.
REFERENCES D. V. Bates, P. T. Macklem and R. V. Christie, Respiratory Funcrion in Disease, 2 Edn., p. 3. W. B. Saunders, Philadelphia, Penn. (1971). P. E. Morrow, F. R. Gibb and K. M. Gazioglu, A study of particulate clearance from the human lungs, Am. Rev. rap. Dis. %, 1209-1221 (1967). R. Santa Cruz, J. Landa, A. Hirsch and M. A. Sackner. Tracheal mucous velocity in normal man and patients with obstructive lung disease. Effects of turbutaline, Am. Rev. resp. Dis. 109, 458-463 (1974). M. Friedman, F. D. Stott, D. Poole, R. Dougherty, G. A. Chapman, H. Watson and M. A. Sackner, A new method of estimating mucous velocity by a roentgenographic technique, Am. Rev. resp. Dis. 113 (SuppI.), 206 (1976). 5. D. B. Yeates, N. Aspin, H. Levison. M. T. Jones and A. C. Bryan, Mucociliary tracheal transport rates in man, J. appl. Physiol. 39, 487-495 (1975). 6. D. B. Yeates, J. M. Sturgess, S. R. Kahn, H. Levison and N. Aspin, Mucociliary transport in trachea of patients with cystic fibrosis, Archs. Dis. Childh. 51, 28-33 (1976). 7. J. W. Wong, T. G. Keens, E. M. Wannamaker, D. N. Crozier. H. Levison and N. Aspin, The effects of gravity on tracheal mucous transport rates in normal subjects and in patients with cystic fibrosis, Pediatrics 60, 146-152 (1977).
About the Author - PAULBASSETT lives with “one foot in the ivory tower and the other in the mud”. He is both a Special Assistant Professor at the Department of Computer Science at York University in Toronto and the president of Sigmatics Corporation Ltd., a Canadian firm specializing in commercial software for mini-computers. He received his BSc. in Mathematics from the University of Toronto in 1967. He joined The Hospital for Sick Children as project leader of the patient monitoring group in 1968 and served as a consultant to them after returning to the University of Toronto to earn his M.Sc. in Computer Science in 1970. About the Author - JOHN W. WONG was born in Hong Engineering Sciences (Physics) in 1974, and his M.S. in
Kong in 1952. He received his B.S. in Medical Biophysics in 1977 from the University of Toronto. He is currently working towards a Ph.D. degree in Medical Biophysics at the University ofToronto. His thesis topic is the study of human mucociliary clearance using radiological and radioactive tracer techniques. About the Author - NORMAN ASPIN
was born in England in 1933. He received his B.Sc. degree in Physics in 1955 from McMaster University in Hamilton, Ontario. After working for a year for a
Human mucociliary clearance physicist with the Hamilton Clinic of the Ontario Cancer Research and Treatment Foundation, he obtained an M.A. in 1957 and a Ph.D. in 1961 in Radiation Physics from the University of Toronto. Since that time he has worked as a medical physicist at the Ontario Cancer Institute and at the Hospital for Sick Children in Toronto. He is an Assistant Professor at the University of Toronto in the Departments of Medical Biophysics, Pediatrics and the Institute of Medical Sciences. His present research interests are centered around the development of techniques for measuring mucociliary clearance rates in airways deep within the human lung.
105
Compur. Biol. Med. Vol. 9, pp. 97-105. 0 Pergamon Press Ltd. 1979. Printed in Great Britain.
w2.co/o
AN INTERACTIVE COMPUTER SYSTEM FOR STUDYING HUMAN MUCOCILIARY CLEARANCE PAUL G. BASSETT Department of Computer Science, York University, Toronto, Ontario, Canada
and JOHN W. WONG and NORMANASPIN The Research Institute, Hospital for Sick Children, Toronto, Canada M5G 1X8 and The Departments of Medical Biophysics and Pediatrics, University of Toronto, Canada (Received 2 May 1978; received for publication 13 September 1978)
Abstract - This paper describes the incorporation of a computer for interactive data collection and analysis into the study of mucous clearance in the human trachea. The success of this system greatly improves the efficiency of data analysis and reduces significantly the possibility of human error that existed in manual operation. Mucociliary clearance framing Peak analysis
Interactive computer system
Structured-FORTRAN
Graphics
Data-
INTRODUCTION The “mucociliary escalator” is one of the major mechanisms by which the lung removes inhaled pollutants. In the lung, cilia are found in the conducting airways, from the trachea (25 mm in dia.), down to the level of the terminal bronchioles (0.65mm in dia.) [l]. These hair-like projections, 5-7 pm in length, cover 3060% of this total surface area, and oscillate in a coordinated whipping fashion so as to sweep along an overlying layer of mucus. The mucus is transported by this ciliary activity from the distal airways up through the trachea, past the larynx, where upon it is swallowed. In this manner, inhaled pollutants that are deposited on the mucous blanket in the airways are removed from the lung. In the past, mucociliary activity has been studied in man by measuring with external scintillation detectors, the half time of disappearance of inhaled radioactive particles from the lung [2]. Such investigations do not provide information on the rates of mucous movement in individual airways. Two methods have been developed to measure such rates in the trachea. One method utilizes a fibre-optic bronchoscope to measure the movement of small teflon discs deposited on top of the tracheal mucus blanket [3]. Since the procedure was invasive, a recent modification has been made whereby fluoroscopy replaced bronchoscopy as the method of detection of the discs [4]. The other method, developed in this laboratory, uses a non-invasive radioisotope imaging technique [5]. The procedure is described below and presented schematically in Fig. 1. The subject takes a dozen breathes from a spirometer system which injects into the latter portion of each breath a dense aerosol mist containing microspheres of albumin labelled with 99mTc. The radioactive microspheres are preferentially deposited by impaction on the bifurcations of the major airways as local aggregations or boluses. These boluses are subsequently cleared by the mucociliary escalator. Using a scintillation camera, many boluses can be observed to move up the trachea in the few hours following deposition of the radioactive microspheres. A rectangular “region of interest” is centered electronically over the image of the trachea. In sequential time intervals or frames, the activity along the tracheal region of interest is displayed on the CRT of a multichannel analyser as a counts vs distance histogram. In this mode of data presentation, a bolus of radioactivity within the trachea appears as a peak in each frame display. By estimating from each film record, the distance of a 97
98
PAULG. BASSETT, JOHNW. WONGand NORMANASPIN SCINTILLATION
IMAGE
..___..____.............. ., 1 CRT OF REGION C ..........______........................... _...,.. .‘-.-...‘... Ia I \ , \ \ I L I I \ SCINTILLATION CAMERA
OF INTEREST
: : : : :
i
’
!
:
a SUBJECT
POLAROID CAMERA
Fig. 1. A schematic presentation of data collection with Polaroid camera in a study of mucous clearance.
peak from the carina at the base of the trachea, and by repeating this measurement over a large number of frames, the rate of bolus movement up the trachea is determined. This technique has been used to measure mucous transport rates in normal subjects [5] and in patients with cystic fibrosis (CF) where mucous secretion and its clearance are considered to be abnormal [6]. It is apparent that the above method of data analysis requires laborious manual determination of the position of a bolus on a large number of Polaroid films. For this reason, the determination of peak position tends to become subjective and prone to error. Moreover, the time required for this analysis is the limiting factor in the number of studies which can be performed. This paper describes an interactive digital computer system for data recording and analysis which overcomes the drawbacks that are inherent in the procedure described above. HARDWARE
AND SOFTWARE
ENVIRONMENT
The physical configuration of the equipment and the flow of data between the components is described as follows : Count data from the region of interest (7.5 cm x 15 cm) is temporarily stored in a buffer memory device (Northern Scientific Inc., NS-625 and NS-630) of the scintillation camera. This data is stored in 64 channels or resolution intervals and is displayed on the CRT of the buffer memory as a histogram of counts vs channel number. The contents of the buffer memory are then transmitted to a time-shared IBM 1800 process control computer through 16 digital input lines of a 1000 ft cable. A computer program which allows for operator intervention in data collection and analysis is filed on a system disc and study data are stored on a removable disc. For direct operator interaction with data processing, a computer connected graphic CRT-keyboard terminal is located beside the scintillation camera. This keyboard is equipped with software implemented, special function keys. The CRT is a Ramtek GX-100 with 512 lines x 256 element resolution which displays data as a histogram of counts vs tracheal distance. Upon completion of a study, a data review mode is provided by the system. A Versa& Matrix Printer is available for copying the processed data from the terminal display. A complete printout of all analysed data can be obtained from the computer line-printer. Within the context of the above hardware environment the following is a brief description of the software environment in which the application programs were developed. The IBM 1800 is equipped with the Multi Programming Executive (MPX) operating system. A considerable amount of additional software has been added by the programming
Human mucociliary clearance
99
staff. This additional support is sufficient to service up to lographic terminals each providing a unique selection of application programs. A graphic language processor or compiler has been implemented which permits a convenient declaration of interactive graphic displays and implements an interface so that the data coming from the terminal can relate directly to the real-time data base. Nestled within this context approximately 40 FORTRAN modules have been designed and implemented using the technique of structured programming. All programs including the MPX operating system and the graphics package are available on disc cartridges. Copies of the discs and the User Manual can be provided (upon request to the authors) to anyone having a similar configuration (including the GX-100 CRT’s). The system’s top level is structured as three modules which: (a) define a study; (b) capture, display, store and statistically analyse the data in real time under a priority interrupt scheme; (c) permit a post-study review of all the data captured and its analysis, with over-ride calculations to re-analyse and/or re-store statistical information about the study. Subsequent sections of this paper outline how these modules are used by the experimenter.
DESCRIPTION
OF STUDY
PROCEDURE
1. Study preparation At the start of a study, the “mucociliary clearance” program is invoked by a START key on the terminal and a disc is mounted for data collection. The system then requests preliminary study parameters as shown in the CRT display of Fig. 2. The subject’s name is entered for identification. The carina and larynx channel numbers in the region of interest are required to specify the fiducial registration points of the trachea. The mm-per-channel provides the current camera calibration and permits a linear conversion from channel numbers to tracheal distance, where the carina channel defines the origin. A time-out interval, or time between data frames is entered as an arbitrary time (usually 60 min) by which the system will terminate data collection if no further data is forthcoming. After entering these parameters, the program is readied for receiving data. To register the limits of the trachea for the system, the positions of the subject’s larynx and carina, as inferred from a chest radiograph of low magnification are first marked on the skin. The subject is then seated in front of the scintillation camera, with two radioactive point
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CAMERA DATFl COLLECTION
FIND STHRT THE STUD?’ TIMER Fig. 2. Study parameters that are entered through the terminal to ready the system. Data collection begins upon hitting of the CAM function key. r.B.M.9 2
R
PAUL G. BASSETT,JOHN W. WONG
100
NORMAN ASPIN
and
sources placed over these markings. The subject is arranged to ensure that the scintillation images from the point sources fall into the region of interest. With the aid of the CRT display of the memory buffer, the larynx and carina channel numbers are determined as the maxima of the two peaks. Two lights are focussed on skin marks on the subject’s back which allows the subject to move away from the camera and to be quickly and accurately repositioned. Once this positioning information is obtained, the point sources are removed and the subject comes out of the seated position for inhalation of the radioactive particles. After deposition of radioactivity, the subject is realigned in his seated position and rigidly supported in front of the scintillation camera. A special function key (CAM) on the terminal keyboard is pressed to start elapsed time counting and data collection. 2. Data collection : time-partitioning
or framing
The time interval between data transmission from the buffer memory to the computer is preset by the operator but can be reset during the course of the study. This time interval or frame usually ranges between 30 and 120s~ and is adjusted to obtain optimal balance between counting statistics and rate of bolus movement. At the start of each frame, the memory buffer is cleared and scintillation counts are accumulated. At the end of each frame, an interrupt is received by the computer from the buffer memory device which initiates the transfer of the buffer contents to the CPU. Each transmission requires approximately 2 msec, during which no scintillation counts are stored. This data is converted into a counts vs tracheal distance histogram and is displayed on the terminal CRT screen upon which the operator can perform real-time data analysis. 3. Data display Figure 3 illustrates a frame display from the terminal screen. Frames are numbered sequentially in order to permit post-study paging (cf. data review). Since each frame results
MUCOCIL
IARY
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CLERRANCE 13
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Fig. 3. A typical data display as seen on the terminal CRT showing a peak at the position of the larynx due to initially impacted radioactivity and a bolus-peak on its course up the trachea. Instructions are provided to aid the operator in real-time data analysis.
101
Human mucociliary clearance
from a relatively long data capture time interval, the elapsed time for a frame is registered as that of the mid-point of the actual time interval. When a bolus of radioactive particles is observed in a particular region of the trachea, it appears in the frame display as a count peak in the corresponding position along the tracheal axis (Fig. 3). There is usually a stationary accumulation ofcounts at the position of the larynx (L) due to impaction of the radioactivity during inhalation. Depending on the amount of radioactivity in the trachea and the choice of frame time, the range of counts during the study may vary by two orders of magnitude. The programs respond by automatically resealing the y-axis for each frame so that the quadrant is completely filled. This enables the user to judge each peak on a relative comparison basis using the maximum available resolution. The cursor field at the bottom of the frame display permits the entry of interactive instructions on the first line, and descriptive comments about the frame on the second line. Through the cursor field, the software design of the system enables the user in real time to locate and store positional information of the bolus-peaks observed in the tracheal distance. 4. Real time data analysis:
peak selection
When a peak appears in a frame (Fig. 3) the peak selection procedure provided by the program enables the system to keep track of the bolus both in time and tracheal position. Since an uneven background count level usually exists, and multiple peaks may be present, the decision as to what constitutes a peak must be made by the experimenter. In order to diminish most effectively the erroneous contribution due to background, a bolus is identified as a peak in the count-distance histogram above the base-line joining two local minima (Fig. 4). It must have a minimum full width half maximum (FWHM) of 1.60cm, which is the resolution of the detector to a 3mm point source of radioactivity. If this definition cannot be
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Fig. 4. A presentation ofa frame display analysed in real time. Two cursors, left and right are used for locating a bolus peak. Position and time data of this peak is stored by giving it a name, B, and pressing a STR function key. Its rate ofmovement up to this frame can be obtained by pressing a FIT function key. Additional comment regarding a frame display can also be stored in the comment field.
PAUL G. BASSETT,JOHNW. WONG and NORMANASPIN
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satisfied due to a high background then arbitrarily the maximum counts in a peak must be at least two standard deviations above the highest local minimum. The terminal has no light pen for peak location purposes. However, a convenient alternative consists of two vertical moveable cursors, as illustrated in Fig. 4. These hairline cursors are initially superimposed in the first frame display (Fig. 3). A function key enables the user to manipulate either one cursor or the other. A small flag at the top indicates which cursor is currently in use. To move a cursor the user makes a coarse adjustment by entering the desired horizontal position (in mm) and pressing the JMP (jump) key. LFT (left) and RGT (right) fine adjustment keys move the active cursor incrementally from the current position to an adjacent observed tracheal count. For defining the limits of a peak in the display, these cursors are positioned over the two adjacent local minima (Fig. 4). For each peak isolated by the two cursors, the program calculates the mid-point, XM, as a weighted average as follows :
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=i=l M
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IC(i) - B(i) 1
i& I W
. X(i)
-
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- W
(r - 1 2 2)
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where 1 and r are the corresponding left and right indicies of the two selected minima, C(i) is the observed count of the peak in the ith position, B(i) is the base-line ordinate in the ith position, X(i) is the distance of the ith position from the carina in mm. A vertical line is drawn through the peak at Xu to indicate its mid-point. In addition, the total counts above the base-line are displayed as shown in Fig. 4. This peak-picking procedure represents one major refinement over the manual approach. It offers a consistent, definitive method of locating the position of a bolus, thus eliminating the error prone method using Polaroid film. Having isolated a particular,peak, the operator types in a single letter name for bolus identification, such as B in Fig. 4, and stores it by depressing the STR function key. Upon receiving this store command, the system looks up the file for the particular bolus name, or creates one if this is a new bolus, and adds to the file a record of the elapsed time of the frame, and the X,,, of the peak. In doing so, the bolus name, and its counts are also added onto the counts versus distance distribution of the frame display. Such updating of the display provides the operator with identifying references during data review. If a bolus should split into two (or the reverse), the resultant boluses are given new letters so that separate transport rate statistics can be maintained. At any time during the study, the following statistics are calculated for any bolus by using the FIT function key: (1) The number of frames in which a particular bolus-peak were observed. (2) The rate of bolus transport based on the slope of the least-squares straight line fitted through the data points of the bolus. (3) The standard error of the rate. (4) The percentage error of the rate. (5) F-ratio, correlation coefficient and r-test as evaluations of the significance of the least square fit through the data points. (6) The standard error of the estimate of the position data. (7) The absolute value of the 95:/, confidence limits of the rate. ,However, only the transport rate of the particular bolus being fitted is shown on the display during the study (Fig. 4). This in-study bolus rate information enables the experimenter to optimize between frame time and counting statistics. The remaining information is available at the completion of the study (cf. data review, Table 1).
5. Data review
A typical study may encompass several hundred frames collected over 3-5 hr. Upon
Human mucociliary clearance
103
Table 1. Summary printout of a study from the computer line-printer
Bolus A B
c D E F
Rate (B) (mm/min) 3.53 3.17 2.25 3.00 1.18 2.03
Frames 29 26 22 19 22 14
R
F ratio 2646.072 8723.484 918.923 532.281 694.660 2384.476
PC E (B) 1.944 1.070 3.298 4.334 3.794 2.047
SE (B) 0.068 0.034 0.074 0.130 0.044 0.041
0.994 0.998 0.989 0.984 0.985 0.997
T-test 51.440 93.399 30.313 23.071 26.356 48.831
SEE 0.251 0.101 0.217 0.335 0.195 0.106
c 0.141 0.070 0.155 0.274 0.093 0.090
Bolus: Name ofa particular bolus. Frames : Number offrames in which a particular bolus was observed. Rate(B): Rate of movement of a bolus as calculated from the least-squares regression fit of all data points. SE (B): The standard error of the rate. PC E (B): The percentage error of the rate. F-Ratio, R (correlation coefficient), T-Test are standard evaluations of significance of the regression line. SEE: The standard error of the estimate of the position data. C: The absolute value of the 95u/, confidence limits of the rate.
completion of a study, a special frame “0” is displayed on the terminal (Fig. 5) summarizing the data which has been stored and analysed. Every selected peak is plotted on a time-displacement scattergram along with all regression lines that have been fitted. This global view of all the collected data represents a tremendous saving of time and of manual effort. It also permits the operator to quickly spot any obvious error made in real time, that in a local context is inconsistent with the overall evolutionary patterns in this display. In a data review mode provided by the system, the operator may page through the recorded frames in any sequence or order that he prefers. Corrections of erroneous choices, or addition of data missed during the study can be made. Upon completion of data review, all statistical calculations on the bolus files are updated and a final conclusive time-displacement scattergram is displayed, similar to that of Fig. 5. As mentioned before, hard copies of any
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Fig. 5. A typical time-displacement scattergram summarizing a)) data analysed during the study. This display is available upon completion of a study and can be updated in the data review mode. Bolus F in this particular display is a rename of bolus E as it underwent a change of rate.
104
PAUL G. BASSETT,
W. WONG and NORMANASPIN
frame displays can be obtained through a Versatec Matrix Printer, thus making the disc available for another study. In addition, a complete printout of all quantitative data collected and bolus statistics are produced by the computer line-printer. Table 1 shows the statistical information available from such a printout. CONCLUSION This paper describes an interactive computer-graphics system which has been used to increase the efficiency and objectivity in analysing data from a study, while reducing the amount of error induced by human effort. The operational simplicity of this radionuclide imaging-computer system for studying mucous clearance has facilitated investigations into a number of clinically interesting problems. For example we have studied the effect of gravity on the mucous transport rates of normal subjects and patients with cystic fibrosis [7). To undertake such studies using the manual approach to data analysis would be too lengthy, tedious, and error prone. Beyond the technical and clinical aspects of this work, we would like to emphasize that biomedical workers can and should expect to benefit from the growing maturity of the software profession. Techniques such as structured programming permit the timely development of reliable programs that provide friendly, convenient interfaces with naive users. Furthermore, hardware costs are now such that interactive techniques, until recently the preserve of well-endowed institutions, are readily available to most people with more modest research grants. Acknowledgements -The authors wish to thank staff of the Department of Clinical Computer Systems, Hospital for Sick Children for their cooperation and Mr. K. Steimann for technical assistance. This work was supported by a grant from the Medical Research Council of Canada.
REFERENCES D. V. Bates, P. T. Macklem and R. V. Christie, Respiratory Funcrion in Disease, 2 Edn., p. 3. W. B. Saunders, Philadelphia, Penn. (1971). P. E. Morrow, F. R. Gibb and K. M. Gazioglu, A study of particulate clearance from the human lungs, Am. Rev. rap. Dis. %, 1209-1221 (1967). R. Santa Cruz, J. Landa, A. Hirsch and M. A. Sackner. Tracheal mucous velocity in normal man and patients with obstructive lung disease. Effects of turbutaline, Am. Rev. resp. Dis. 109, 458-463 (1974). M. Friedman, F. D. Stott, D. Poole, R. Dougherty, G. A. Chapman, H. Watson and M. A. Sackner, A new method of estimating mucous velocity by a roentgenographic technique, Am. Rev. resp. Dis. 113 (SuppI.), 206 (1976). 5. D. B. Yeates, N. Aspin, H. Levison. M. T. Jones and A. C. Bryan, Mucociliary tracheal transport rates in man, J. appl. Physiol. 39, 487-495 (1975). 6. D. B. Yeates, J. M. Sturgess, S. R. Kahn, H. Levison and N. Aspin, Mucociliary transport in trachea of patients with cystic fibrosis, Archs. Dis. Childh. 51, 28-33 (1976). 7. J. W. Wong, T. G. Keens, E. M. Wannamaker, D. N. Crozier. H. Levison and N. Aspin, The effects of gravity on tracheal mucous transport rates in normal subjects and in patients with cystic fibrosis, Pediatrics 60, 146-152 (1977).
About the Author - PAULBASSETT lives with “one foot in the ivory tower and the other in the mud”. He is both a Special Assistant Professor at the Department of Computer Science at York University in Toronto and the president of Sigmatics Corporation Ltd., a Canadian firm specializing in commercial software for mini-computers. He received his BSc. in Mathematics from the University of Toronto in 1967. He joined The Hospital for Sick Children as project leader of the patient monitoring group in 1968 and served as a consultant to them after returning to the University of Toronto to earn his M.Sc. in Computer Science in 1970. About the Author - JOHN W. WONG was born in Hong Engineering Sciences (Physics) in 1974, and his M.S. in
Kong in 1952. He received his B.S. in Medical Biophysics in 1977 from the University of Toronto. He is currently working towards a Ph.D. degree in Medical Biophysics at the University ofToronto. His thesis topic is the study of human mucociliary clearance using radiological and radioactive tracer techniques. About the Author - NORMAN ASPIN
was born in England in 1933. He received his B.Sc. degree in Physics in 1955 from McMaster University in Hamilton, Ontario. After working for a year for a
Human mucociliary clearance physicist with the Hamilton Clinic of the Ontario Cancer Research and Treatment Foundation, he obtained an M.A. in 1957 and a Ph.D. in 1961 in Radiation Physics from the University of Toronto. Since that time he has worked as a medical physicist at the Ontario Cancer Institute and at the Hospital for Sick Children in Toronto. He is an Assistant Professor at the University of Toronto in the Departments of Medical Biophysics, Pediatrics and the Institute of Medical Sciences. His present research interests are centered around the development of techniques for measuring mucociliary clearance rates in airways deep within the human lung.
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