A flexible multivariate random effects proportional odds model with application to adverse effects during radiation therapy

TL;DR

This paper introduces a new flexible multivariate random effects proportional odds model to analyze longitudinal mucositis severity across different mouth sites during radiation therapy, accounting for dose and individual variability.

Contribution

The paper develops a novel extension of the proportional odds model that incorporates multivariate responses, random effects, and non-linear dose effects for analyzing mucositis data.

Findings

Different mouth sites show varying sensitivity to radiation-induced mucositis.

Cumulative radiation dose and mouth site are the strongest predictors of mucositis severity.

Age and gender have negligible effects on mucositis scores.

Abstract

Radiation therapy in patients with head and neck cancer has a toxic effect on mucosa, the soft tissue in and around the mouth. Hence mucositis is a serious common side effect and is a condition characterized by pain and inflammation of the surface of the mucosa. Although the mucosa recovers during breaks of and following the radiotherapy course the recovery will depend on the type of tissue involved and on its location. We present a novel flexible multivariate random effects proportional odds model which takes account of the longitudinal course of oral mucositis at different mouth sites and of the radiation dosage (in terms of cumulative dose). The model is an extension of the {\em proportional odds model} which is used for ordinal response variables. Our model includes the ordinal multivariate response of the mucositis score by location, random intercepts for individuals and includes a non-linear function of cumulative radiation dose. The model allows to test whether sensitivity differs by mouth sites after having adjusted for site specific cumulative radiation dose. The model also allows to check whether and how the (non-linear) effect of site specific dose differs by site. We fit the model to longitudinal patient data from a prospective observation and find that after adjusting for cumulative dose, upper, lower lips and mouth floor are associated with the lowest mucositis scores and hard and soft palate are associated with the highest mucositis scores. This implies the possibility that tissues at different mouth locations differ in their sensitivity to the toxic effect of radiation. We also find that cumulative dose followed by mouth site are the strongest predictors of mucositis, and the effects of age and gender are negligible.