Examining factors related to low performance of predicting remission in participants with major depressive disorder using neuroimaging data and other clinical features

Major depressive disorder (MDD), a prevalent mental health issue, affects more than 8% of the US population, and almost 17% in the young group of 18–25 years old. Since Covid-19, its prevalence has become even more significant. However, the remission (being free of depression) rates of first-line antidepressant treatments on MDD are only about 30%. To improve treatment outcomes, researchers have built various predictive models for treatment responses and yet none of them have been adopted in clinical use. One reason is that most predictive models are based on data from subjective questionnaires, which are less reliable. Neuroimaging data are promising objective prognostic factors, but they are expensive to obtain and hence predictive models using neuroimaging data are limited and such studies were usually in small scale (N<100). In this paper, we proposed an advanced machine learning (ML) pipeline for small training dataset with large number of features. We implemented multiple imputation for missing data and repeated K-fold cross validation (CV) to robustly estimate predictive performances. Different feature selection methods and stacking methods using 6 general ML models including random forest, gradient boosting decision tree, XGBoost, penalized logistic regression, support vector machine (SVM), and neural network were examined to evaluate the model performances. All predictive models were compared using model performance metrics such as accuracy, balanced accuracy, area under ROC curve (AUC), sensitivity and specificity. Our proposed ML pipeline was applied to a training dataset and obtained an accuracy and AUC above 0.80. But such high performance failed while applying our ML pipeline using an external validation dataset from the EMBARC study which is a multi-center study. We further examined the possible reasons especially the site heterogeneity issue.