System and method for statistical analysis of QT interval as a function of changes in RR interval
View Patent ↗A system and method for statistically analyzing QT interval as a function of changes in the RR interval. The system and method utilize three statistical comparisons to fully characterize the QT response: (1) the comparison of curves to give an overall effect; (2) the incidence of points exceeding a baseline upper 95% single-point prediction bound to reflect the degree of heterogeneity of ventricular repolarization; and (3) the magnitude of these points to provide a quantitative assessment of treatment-induced changes in the QT-RR relationship. The system and method use the relationship between the QT interval and heart rate (RR interval) to reference a control baseline response. Data from mammals such as humans and dogs, and pharmacological maneuvers using both cardiac and non-cardiac therapeutic agents, may be used with this multi-parameter statistical system and method. Additionally, the system and method quantifies the incidence and magnitude of points lying outside the upper 95% single-point prediction limit of the regression analysis for vehicle versus treatment.
1. A computer-implemented method for statistical analysis of QT interval as a function of changes in the RR interval before and after administration of a dose of a compound, the method comprising the steps of:
comparing a pre-dose curve of QT interval versus RR interval to a post-dose curve of QT interval versus RR interval;
determining the incidence of points of the post-dose curve that exceed an upper single-point prediction limit of the pre-dose curve to determine the degree of heterogeneity of ventricular repolarization; and
determine the magnitude that these points exceed the pre-dose QT curve and provide a quantitative assessment of treatment-induced changes in the QT-RR relationship.
2. A computer-implemented method as recited in claim 1 , wherein the pre-dose curve to post-dose curve comparison step comprises the substeps of:
using an equation to fit each QT measurement to a preceding, or set of preceding, RR intervals and provide the pre-dose curve and post-dose curves; and
comparing the pre-dose and post-dose curves to determine if and at what point the post-dose curve becomes significantly higher than the pre-dose curve.
3. A computer-implemented method as recited in claim 1 , wherein the compound is administered to a human.
4. A computer-implemented method as recited in claim 1 , wherein the determining step comprises the substeps of:
pooling the confidence limits for the pre-dose and post-dose curves to provide an estimate of the standard error of the difference between the two curves;
using the single-point upper 95% prediction limit for the pre-dose curve to determine whether a QT point on the post-dose curve is significantly prolonged;
conducting a repeated measures test for significance to evaluate an overall effect of the treatment over all of the time periods; and
conducting individual significance tests of the proportion of prolonged outliers to determine if the treatment response is significantly higher than the pre-dose curve.
5. A computer-implemented method as recited in claim 1 , wherein the step of comparing the points of the post-dose data that exceed the upper 95% single-point prediction limit to the pre-dose curve comprises the substeps of:
comparing outliers to the pre-dose curve to estimate how far above the pre-dose curve they are prolonged;
subtracting the post-dose outliers from the pre-dose curve to provide corrected .DELTA.QT values; comparing the corrected .DELTA.QT values within treatment groups, post-dose to pre-dose, and across treatments;
conducting an overall test to compare the mean .DELTA.QT of each group; and conducting a one-sided significance test on the .DELTA.QT values.
6. A computer readable medium that stores instructions executable by one or more processors to perform statistical analysis of QT interval as a function of changes in the RR interval before and after administration of a dose of a compound, the computer-readable medium comprising:
instructions for comparing a pre-dose curve of QT interval versus RR interval to a post-dose curve of QT interval versus RR interval;
instructions for determining the incidence of points of the post-dose curve that exceed an upper 95% single-point prediction limit to determine the degree of heterogeneity of ventricular repolarization; and
instructions for comparing the points of the post-dose data that exceed the upper 95% single-point prediction limit to the pre-dose curve to determine the magnitude of these points and provide a quantitative assessment of treatment-induced changes in the QT-RR relationship.
7. A computer readable medium as recited in claim 6 , wherein the instructions for comparing the pre-dose curve to post-dose curve comprise:
instructions for using an equation to fit each QT measurement to a preceding RR interval and provide the pre-dose curve and post-dose curves; and
instructions for comparing the pre-dose and post-dose curves to determine if and at what point the post-dose curve becomes significantly higher than the pre-dose curve.
8. A computer readable medium as recited in claim 6 , wherein the compound is administered to a human.
9. A computer readable medium as recited in claim 6 , wherein the instructions for determining the incidence of points of the post-dose data that exceed the upper 95% single-point prediction limit comprise:
instructions for pooling the confidence limits for the pre-dose and post-dose curves to provide an estimate of the standard error of the difference between the two curves;
instructions for using the upper 95% single-point prediction limit for the pre-dose curve to determine whether a QT point on the post-dose curve is significantly prolonged;
instructions for conducting a repeated measures test for significance to evaluate an overall effect of the treatment; and
instructions for conducting individual significance tests of the proportion of prolonged outliers to determine if treatment is significantly higher than the pre-dose curve.
10. A computer readable medium as recited in claim 6 , wherein the instructions for comparing the points of the post-dose data that exceed the upper 95% single-point prediction limit to the pre-dose curve comprise:
instructions for comparing outliers to the pre-dose curve to estimate how far above the pre-dose curve they are prolonged;
instructions for subtracting the data of the post-dose curve from the data of the pre-dose curve to provide corrected .DELTA.QT values;
instructions for comparing the corrected .DELTA.QT values between treatments; and
instructions for conducting an overall test to compare the magnitudes of each treatment .DELTA.QT.
11. A system for statistical analysis of QT interval as a function of changes in the RR interval before and after administration of a dose of a compound, the system comprising:
a means for comparing a pre-dose curve of QT interval versus RR interval to a post-dose curve of QT interval versus RR interval, determining the incidence of points of the post-dose data that exceed an upper 95% single-point prediction limit to determine the degree of heterogeneity of ventricular repolarization, and
a means for comparing the points of the post-dose data that exceed the upper 95% single-point prediction limit of the pre-dose curve to determine the magnitude of these points and provide a quantitative assessment of treatment-induced changes in the QT-RR relationship.
12. A system as recited in claim 11 , wherein the means for comparing the pre-dose curve to post-dose curve further:
uses an equation to fit each QT measurement data to the corresponding preceding RR interval measurement data and provide the pre-dose curve and post-dose curves; and
compares the pre-dose and post-dose curves to determine if and at what point the post-dose curve becomes significantly higher than the pre-dose curve.
13. A system as recited in claim 11 , wherein the compound is administered to a human.
14. A system as recited in claim 11 , wherein the means for determining the incidence of points of the post-dose curve that exceed the upper 95% single-point prediction limit further:
pools the confidence limits for the pre-dose and post-dose curves to provide an estimate of the standard error of the difference between the two curves;
uses the upper 95% single-point prediction limit for the pre-dose curve to determine whether a QT point on the post-dose curve is significantly prolonged; and
conducts a repeated measures test for significance to evaluate an overall effect of the compound over all of the time periods; and instructions for conducting individual significance tests of the proportion of prolonged outliers to determine if any one dose of the treatment is significantly higher than the pre-dose curve.
15. A system as recited in claim 11 , wherein the means for comparing the points of the post-dose curve that exceed the upper 95% single-point prediction limit to the pre-dose curve further:
compares outliers to the pre-dose curve to estimate how far above the pre-dose curve they are prolonged;
subtracts the post-dose data from the pre-dose curve to provide corrected QT values (.DELTA.QT);
compares the corrected QT values within treatment groups, post-dose to pre-dose, and across treatment groups; and
conducts an overall test to compare the magnitudes of each group.