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A two-part mixture model for longitudinal adverse event severity data
We fit a mixed effects logistic regression model to longitudinal adverse event (AE) severity data (four-point ordered categorical response) to describe the dose-AE severity response for an investigational drug. The distribution of the predicted interindividual random effects (Bayes predictions) was...
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Published in: | Journal of pharmacokinetics and pharmacodynamics 2003-10, Vol.30 (5), p.315-336 |
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container_title | Journal of pharmacokinetics and pharmacodynamics |
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creator | KOWALSKI, Kenneth G MCFADYEN, Lynn HUTMACHER, Matthew M FRAME, Bill MILLER, Raymond |
description | We fit a mixed effects logistic regression model to longitudinal adverse event (AE) severity data (four-point ordered categorical response) to describe the dose-AE severity response for an investigational drug. The distribution of the predicted interindividual random effects (Bayes predictions) was extremely bimodal. This extreme bimodality indicated that biased parameter estimates and poor predictive performance were likely. The distribution's primary mode was composed of patients that did not experience an AE. Moreover, the Bayes predictions of these non-AE patients were nearly degenerative, i.e., the predictions were nearly identical. To resolve this extreme bimodality we propose using a two-part mixture modeling approach. The first part models the incidence of AE's, and the second part models the severity grade given the patient had an AE. Unconditional probability predictions are calculated by mixing the incidence and severity model probability predictions. We also report results of simulation studies, which assess the predictive and statistical (bias and precision) performance of our approach. |
doi_str_mv | 10.1023/b:jopa.0000008157.26321.3c |
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The distribution of the predicted interindividual random effects (Bayes predictions) was extremely bimodal. This extreme bimodality indicated that biased parameter estimates and poor predictive performance were likely. The distribution's primary mode was composed of patients that did not experience an AE. Moreover, the Bayes predictions of these non-AE patients were nearly degenerative, i.e., the predictions were nearly identical. To resolve this extreme bimodality we propose using a two-part mixture modeling approach. The first part models the incidence of AE's, and the second part models the severity grade given the patient had an AE. Unconditional probability predictions are calculated by mixing the incidence and severity model probability predictions. We also report results of simulation studies, which assess the predictive and statistical (bias and precision) performance of our approach.</description><identifier>ISSN: 1567-567X</identifier><identifier>EISSN: 1573-8744</identifier><identifier>DOI: 10.1023/b:jopa.0000008157.26321.3c</identifier><identifier>PMID: 14977163</identifier><language>eng</language><publisher>Dordrecht: Springer</publisher><subject>Bayes Theorem ; Biological and medical sciences ; Clinical Trials, Phase III as Topic - adverse effects ; Clinical Trials, Phase III as Topic - methods ; Clinical Trials, Phase III as Topic - statistics & numerical data ; Drugs, Investigational - adverse effects ; General pharmacology ; Humans ; Logistic Models ; Longitudinal Studies ; Medical sciences ; Miscellaneous ; Pharmacology. 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The distribution of the predicted interindividual random effects (Bayes predictions) was extremely bimodal. This extreme bimodality indicated that biased parameter estimates and poor predictive performance were likely. The distribution's primary mode was composed of patients that did not experience an AE. Moreover, the Bayes predictions of these non-AE patients were nearly degenerative, i.e., the predictions were nearly identical. To resolve this extreme bimodality we propose using a two-part mixture modeling approach. The first part models the incidence of AE's, and the second part models the severity grade given the patient had an AE. Unconditional probability predictions are calculated by mixing the incidence and severity model probability predictions. We also report results of simulation studies, which assess the predictive and statistical (bias and precision) performance of our approach.</description><subject>Bayes Theorem</subject><subject>Biological and medical sciences</subject><subject>Clinical Trials, Phase III as Topic - adverse effects</subject><subject>Clinical Trials, Phase III as Topic - methods</subject><subject>Clinical Trials, Phase III as Topic - statistics & numerical data</subject><subject>Drugs, Investigational - adverse effects</subject><subject>General pharmacology</subject><subject>Humans</subject><subject>Logistic Models</subject><subject>Longitudinal Studies</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Pharmacology. 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subjects | Bayes Theorem Biological and medical sciences Clinical Trials, Phase III as Topic - adverse effects Clinical Trials, Phase III as Topic - methods Clinical Trials, Phase III as Topic - statistics & numerical data Drugs, Investigational - adverse effects General pharmacology Humans Logistic Models Longitudinal Studies Medical sciences Miscellaneous Pharmacology. Drug treatments Predictive Value of Tests Studies |
title | A two-part mixture model for longitudinal adverse event severity data |
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