Components of variability in digitized M-mode echocardiography : applied to monitoring of Adriamycin cardiotoxicity
Creators: name: Schumacher, Peter Michael
Publisher: name: University of British Columbia
Year: 2010

description: This work concerns the use of M-mode echocardiography, a medical diagnostic technique based on sound wave imaging, in the assessment of the degree of impairment of heart function in children. One cause of left ventricular (LV) impairment is Adriamycin (doxorubicin), a drug used commonly in the treatment of cancer. Although many investigators have used echocardiography (ECHO) to monitor cardiac damage due to Adriamycin (ADM), the magnitude of long-term longitudinal or serial changes one can expect in a typical healthy child's readings has not been assessed. This knowledge might be useful in monitoring. We designed and carried out a study with 18 healthy children to: (i) quantify the longitudinal variation in ECHO parameters between successive months, and compare this to short-term (minutes) serial variation and to between-subject variability; (ii) compare different ECHO measures with respect to these types of variability, as well as on the basis of measurement accuracy; (iii) compare short-term serial variation with that due to the measurement process, with the aim of increasing the precision of a reading; (iv) examine whether subject age and sex have any bearing on the readings. Our ECHO variables consist of 4 measures of change in cardiac dimension between systole and diastole, 6 peak velocities and 6 peak normalized velocities. We used a 4-factor hierarchal factorial design. To address (i) to (iii) above, the data were analyzed in a univariate fashion with a variance components model. It was found that: (a) between-subject variation accounts for the largest proportion of total variability; (b) within-subject monthly longitudinal variation is substantial, and approaches the magnitude of that between subjects; (c) variation between successive months is markedly larger than the short-term variability; (d) tracing variation, a type of measurement error, is negligible in comparison with short-term variation, implying that the precision of a reading can be improved more by analyzing additional heartbeats than by replicating the analysis of each beat; (e) the LV shortening fraction is more stable over time and is subject to less measurement error than the peak systolic and peak diastolic velocities of the LV, the septal, or the posterior walls. To address (iv) above, we performed an Analysis of Covariance for each variable. Subject sex was found to have no bearing on ECHO readings. There is some indication that some of the measures are linearly related to subject age. In addition, these data were combined with single ECHO measurements on 33 other healthy children to yield 95% prediction intervals for normal ECHO parameters; 95% bounds for normal monthly differences in the values were also obtained. Together with serial data on 25 children being treated with ADM, we attempted to identify which ECHO variables would be more useful in monitoring for LV dysfunction. As well as taking into account the relative sensitivities of the variables to ADM, we found the smallest set of measures which would collectively identify all children displaying abnormal (drops in) LV function. This was formulated and solved as an integer programming problem. Lastly, a Factor Analysis was used in an attempt to reveal the dimensionality of normal LV function. Apparently the major impact of ADM on LV function occurs during the first half of therapy. Many patients are marginally within normal bounds at mid-therapy, even though they may exhibit abnormally large changes since onset. Based on the above criteria, we tentatively recommend the following ECHO measures as potentially useful for monitoring of ADM cardiotoxicity: ejection fraction (shortening fraction may be used equivalently), systolic percent change of the septal and posterior wall thicknesses, peak (normalized) LV diastolic velocity, peak posterior wall systolic and normalized diastolic velocities, and peak septal wall diastolic velocity.